Immune Control of HIV
Muthukumar Balasubramaniam, Jui Pandhare, and Chandravanu Dash
Author Information

1Center for AIDS Health Disparities Research, 

2Department ofBiochemistry and Cancer Biology

3School of Graduate Studies and Research, Meharry Medical College,Nashville, TN – 37208. USA.

*Corresponding AuthorsCorrespondence: cdash@mmc.edu,  muthukumarb@mmc.edu


Citation Information
Balasubramaniam et al. JoLS Vol. 1, No. 1, June 2019:4-37 http://doi.org/c82v, PMID: 31468033, PMCID: PMC6714987

Abstract

The human immunodeficiency virus (HIV) infection of the immune cells expressing the cluster of differentiation 4 cell surface glycoprotein (CD4+ cells) causes progressive decline of the immune system and leads to the acquired immunodeficiency syndrome (AIDS). The ongoing global HIV/AIDS pandemic has already claimed over 35 million lives. Even after 37 years into the epidemic, neither a cure is available for the 37 million people living with HIV (PLHIV) nor is a vaccine discovered to avert the millions of new HIV infections that continue to occur each year. If left untreated, HIV infection typically progresses to AIDS and, ultimately, causes death in a majority of PLHIV. The recommended combination antiretroviral therapy (cART) suppresses virus replication and viremia, prevents or delays progression to AIDS, reduces transmission rates, and lowers HIV-associated mortality and morbidity. However, because cART does not eliminate HIV, and an enduring pool of infected resting memory CD4+ T cells (latent HIV reservoir) is established early on, any interruption to cART leads to a relapse of viremia and disease progression. Hence, strict adherence to a life-long cART regimen is mandatory for managing HIV infection in PLHIV. The HIV-1-specific cytotoxic T cells expressing the CD8 glycoprotein (CD8+ CTL) limit the virus replication in vivo by recognizing the viral antigens presented by human leukocyte antigen (HLA) class I molecules on the infected cell surface and killing those cells. Nevertheless, CTLs fail to durably control HIV-1 replication and disease progression in the absence of cART. Intriguingly,1% of cART-naive HIV-infected individuals called elite controllers/HIV controllers (HCs) exhibit the core features that define a HIV-1 “functional cure” outcome in the absence of cART: durable viral suppression to below the limit of detection, long-term non-progression to AIDS, and absence of viral transmission. Robust HIV-1-specific CTL responses and prevalence of protective HLA alleles associated with enduring HIV-1 control have been linked to the HC phenotype. An understanding of the molecular mechanisms underlying the CTL-mediated suppression of HIV-1 replication and disease progression in HCs carrying specific protective HLA alleles may yield promising insights towards advancing the research on HIV cure and prophylactic HIV vaccine.

Keywords: HIV, PLHIV, AIDS, cART, CD4+ T cells, CD8+ T cells, Latency, HLA, CTL, Functional cure, HIV controllers, Elite Controllers.


INTRODUCTION

The human immunodeficiency virus (HIV) targets immune cells expressing the cluster of differentiation 4 cell surface glycoprotein (CD4+ cells), which include T cells (1) (3) , macrophages (4) (7) , and dendritic cells (8) (10) , and establishes a permanent infection by inserting the double-stranded DNA copy (vDNA) of its RNA genome into the target cell chromosome (11). The chromosomally-integrated vDNA (termed “provirus”) persists for the lifetime of the host cell and gives rise to progeny viruses. If left untreated, in majority of HIV-infected individuals (chronic progressors, CPs), continuous production of progeny virus from the provirus causes de novo infections and target cell death (12) (14) . The resulting progressive failure of the immune system leads to the development of acquired immunodeficiency syndrome (AIDS) and, ultimately, death (15). Consequently, HIV has already claimed over 35 million lives due to AIDS-related opportunistic infections and cancers. There are two types of HIV: type 1 (HIV-1) and type 2 (HIV-2) (16) (17) . The HIV-1, which accounts for over 95% infections worldwide, is the virus responsible for the ongoing HIV/AIDS pandemic, whereas the relatively less pathogenic HIV-2 is endemic to West Africa. The lack of an effective preventive HIV vaccine (18-20), despite decades of intense research, is resulting in millions of new HIV infections every year; globally, 1.8 million people were infected with HIV in 2017. Antiretroviral drugs (ARVs) that target and inhibit the function of specific HIV-1 proteins and, consequently, certain stages of virus life cycle are currently the only treatment option for the 37 million people living with HIV (PLHIV) (21). The standard of care is a combination antiretroviral therapy (cART) involving a cocktail of ARVs aimed to manage pre-existing or minimize post-therapy emergence of drug-resistant viral strains (22-27), which result from the low fidelity HIV-1 replication process and/or host factor-induced mutations in viral genome (28-30). Since its introduction in 1996, cART has been highly effective in suppressing HIV-1 replication, impeding disease progression, partially preserving or restoring the immune competence, and minimizing the risk of transmission (31) (33) . Yet, cART blocks only the de novo infection of susceptible cells, but not the virus production from proviruses in the infected cells. Aggravatingly, a population of long-lived resting memory CD4+ T cells (rCD4s) harboring transcriptionally silent, and consequently non-replicating, provirus (latent HIV reservoir) is established very early in HIV-1 infection (34-37). The cART does not eliminate the provirus (38) , and hence any interruption of cART leads to rapid resumption of HIV-1 replication within days to weeks (39). (40) Therefore, cART is not curative and must be administered uninterrupted for life. HIV-1-specific cytotoxic T-lymphocytes (CTL) expressing the cluster of differentiation 8 cell surface glycoprotein (CD8+) represent the most critical host immune response limiting HIV-1 replication in vivo (41). The CTLs eliminate HIV-infected cells by first recognizing specific viral peptides presented by human leukocyte antigen (HLA) class I molecules on the cell surface and then activating effector mechanisms that cause cell killing. Nevertheless, in the case of untreated CPs, CTLs fail to durably control virus replication and prevent progression to AIDS. This failure of the CTL-mediated viral control stems from a combination of viral strategies designed to pre-empt or evade the CTL response. Prominent among them is the establishment of latent HIV reservoirs that are deficient in viral antigen production and hence are impervious to CTL-mediated immune responses (42). Therefore, the latent HIV reservoirs present the greatest barrier to HIV cure (43).

Disconcertingly, 37 years into the epidemic, no curative treatment is currently available for the 37 million PLHIV. Consequently, close to a million people continue to die of AIDS-related illnesses every year. The “HIV care continuum”- a framework outlining the recommended steps of medical care for PLHIV, entails testing and diagnosis, linkage to and retention in clinical care, initiation of and adherence to cART, and viral suppression (44-45). However, 1 in 4 of the PLHIV (i.e. over 9 million individuals) are unaware of their HIV-1 status, and only around 60% of the PLHIV (~21 million individuals) are currently accessing cART. Further, two-thirds of the PLHIV (over 25 million individuals) reside in resource-limited settings of sub-Saharan Africa, which presents significant barriers to effective implementation of the HIV care continuum. Therefore, the HIV/AIDS pandemic is likely to continue to be a significant public health crisis in the foreseeable future for the following reasons: (1) requirement of and strict adherence to life-long cART regimen, even in the face of significant long-term side effects, (2) increasing rates of comorbid non-AIDS-related diseases (cardiovascular, liver, kidney) and disorders (neurocognitive) in PLHIV due to persistent and elevated immune activation and inflammation despite cART-induced viral suppression, and (3) the uncertainty of the timeline, let alone the prospects, of the availability of effective, viable, and scalable curative strategies targeting HIV. Hence, despite the associated scientific and logistical challenges, it is imperative that the scientific community and the funding agencies pursue the path towards developing curative strategies to tackle HIV (46).

Remarkably, the HIV-1 replication is robustly and durably suppressed, the viral load is maintained below the clinical detection limit, and the disease progression is prevented over long-term in a small subset ((1%) of untreated (cART-naïve) HIV-infected individuals called elite controllers/HIV controllers (HCs) (47) (48) . Despite the reported genetic and immunologic heterogeneity amongst HCs, robust HIV-1-specific CTL responses have been demonstrated to play a key role in controlling HIV-1 infection in HCs. Further, certain HLA alleles associated with enduring control of HIV-1 replication and long-term non-progression to AIDS are prevalent in HCs, whose CTLs display superior functional avidity (ability to recognize very low concentrations of HIV-specific antigens) and polyfunctionality (ability to secrete multiple cytokines) in countering HIV-infected cells. This illustrates that the human immune response, albeit in select human population, can mount a robust and enduring control of HIV-1 replication and prevent progression to AIDS, even in the absence of cART. Because HCs exhibit the core features that define a HIV-1 “functional cure” outcome, i.e. durable suppression of viral replication, absence of viral transmission, and non-progression to AIDS- all in the absence of cART, they have been proposed as a model for HIV cure research.

This review is directed at a broader readership in life sciences with the primary aim of providing an overview of the evolving challenges and opportunities in the ongoing research activities directed towards HIV cure. In this review, we start by drawing the reader’s attention to the origin and types of HIV because any discussion on HIV cure or elimination at the clinical or population level must be cognizant of the existence of animal reservoirs (40 different simian immune deficiency viruses, two of which gave rise to HIV) (16) (49) (50) and the clinically-significant HIV subtype-specific variances in the HIV pathogenesis, transmission, and drug resistance (51-54). We then provide a primer on the architecture, genome, and proteome of HIV-1, an outline of the HIV-1 replication cycle in the host cell, and a rundown on HIV-1 pathogenesis, so as to highlight how the virus make-up, replication strategy, and pathogenesis is geared towards establishing a permanent and immune-evasive infection in the host. The overviews of the HIV-1 latency, the ongoing research on HIV-1 cure, and the HIV-specific CTL response are leads to the discussion about how specific HLA alleles in the HCs contribute to the CTL-mediated durable suppression of virus replication and disease progression, and how a better understanding of the underlying molecular mechanisms may help advance scientific research efforts towards an HIV cure.


ORIGIN AND TYPES OF HIV

AIDS was diagnosed and recognized as a new disease in 1981 in the USA (55) (56)with the subsequent discovery of HIV-1 as the causative agent in 1983 (57). The two types of HIV identified to date, HIV-1 and HIV-2, display similar morphology, tropism, and modes of transmission; however, they are genetically and antigenically divergent (58) (59). HIV-1 is responsible for over 95% infections worldwide, and the different strains of HIV-1 are classified into four groups: major (M), non-outlier (N), outlier (O), and P (60-63). The group M HIV-1 is the predominant circulating strain responsible for >90% infections worldwide, and hence, for the global HIV/AIDS epidemic; viruses belonging to the other three groups are endemic in certain African countries and cause fewer infections. HIV arose from cross-species zoonotic transmissions of simian immunodeficiency viruses (SIV) from monkeys to great apes and ultimately to humans (16) (64) (65). Four independent cross-species transmissions of SIV from chimpanzees (SIVcpz) or gorillas (SIVgor) to humans gave rise to the four HIV-1 groups: M and N from SIVcpz, and O and P from SIVgor. Notably, the pandemic HIV-1 group M strain arose in Cameroon almost a century ago from a single transmission event involving an SIVcpz-infected chimpanzee and a human. The group M strains are further classified into nine subtypes (A, B, C, D, F, G, H, J, and K); each subtype is genetically distinct but phylogenetically equidistant from each other. Two or more of these subtypes can further recombine their genetic material to generate mosaic strains known as circulating recombinant forms (CRFs); around 97 CRFs have been reported to date. The globally dominant HIV-1 subtype C accounts for nearly 50% infections worldwide and is concentrated in Southern Africa and India. The HIV-1 subtype B is dominant in the Americas, Western Europe, and Australasia, and accounts for around 10% global infections. Unlike HIV-1, HIV-2 is largely endemic in West Africa (16) (66) (67), although the virus has spread to other parts of world in the past decade (17). Approximately 1-2 million of the PLHIV are infected with HIV-2. The different strains of HIV-2 are classified into nine different groups- A to I, which arose from nine independent cross-species transmission events involving the SIV from sooty mangabey monkeys (SIVsmm). Relative to HIV-1 infection, HIV-2 infection is generally marked by lower viral load, longer asymptomatic period, slower target cell depletion and disease progression, and lower transmission rates (68-75). However, in the absence of cART, HIV-2 infection eventually leads to AIDS and, ultimately, death (76).

HIV-1 ARCHITECTURE, GENOME, AND PROTEOME

The infectious HIV-1 (virion) is a spherical-shaped particle measuring ~120 nm in diameter and consisting of an outer host cell-derived lipid bilayer membrane and an inner core (77). The viral core comprises of a conical-shaped protein shell termed capsid (78) that encases a ribonucleoprotein (RNP) complex of two non-covalently attached copies of the ~9.7 kb-sized positive-sense single-stranded (ss) viral RNA genome (vRNA), certain viral and host proteins, and the host cellular tRNALys (79). The highly structured vRNA harbors several cis-acting structural elements and nine open-reading frames (ORF) (80). The three major ORFs- gag, pol, and env, code for the polyprotein precursors of structural proteins [matrix (MA), capsid (CA), nucleocapsid (NC), and p6], enzymes [protease (PR), reverse transcriptase (RT), and integrase (IN)], and envelope proteins [glycoprotein 120 (gp120) and glycoprotein 41 (gp41)], respectively. The remaining six ORFs encode regulatory [trans-activator of transcription protein (tat) and regulator of expression of viral proteins (Rev)] or accessory [negative factor (Nef), viral protein R (Vpr), viral protein U (Vpu), and virion infectivity factor (Vif)] viral proteins. These viral proteins are synthesized only after the DNA copy of the HIV genome is integrated into the host chromosome and then transcribed into viral mRNAs. The polymorphic capsid is composed of ~200-250 hexamers and 12 pentamers of the 24 kDa CA protein, and contains multiple copies of RT, IN, PR, NC, MA, and Vpr (81). Approximately 7-14 Env spikes, each comprised of three copies of non-covalently linked heterodimers of viral gp120 and gp41, are anchored in the outer viral membrane (82-84). The Env spike determines the HIV-1 target cell tropism, i.e. CD4+ cells (85-88) and, being the only viral protein exposed on the surface of the virus particle, is the primary target of the neutralizing antibodies (20) (89-93).

HIV-1 REPLICATION

HIV-1 primarily targets and infects the CD4+ T helper cells, macrophages, and dendritic cells in humans. HIV-1 replication in target cells is broadly categorized into two phases: early and late (94). Besides the virus-encoded proteins, HIV-1 is extensively dependent on the host cell machinery and proteins for productive replication (95). Remarkably, over 2000 host cellular proteins, termed host-dependency factors (HDFs), have been implicated in HIV-1 replication cycle (96). Conversely, HIV-1 also employs its genome and proteome to effectively thwart the barriers imposed by host-encoded restriction factors (97). The early phase begins with the Env-mediated adhesion of the virus particle onto certain cell attachment factors present on the surface of the target cells. The viral Env has been shown to adhere to the heparan sulfate proteoglycans on macrophages (98), α4β7 integrin on T cells (99) (100), and dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) on dendritic cells (101) (102). This enables the viral surface subunit protein gp120 to sequentially bind to the CD4 receptor (85-87) and one of the chemokine receptors, C-C chemokine receptor type 5 (CCR5)- the preferred coreceptor of the transmitted form of HIV-1, or C-X-C chemokine receptor type 4 (CXCR4), on the target cell surface (103-106) The ensuing conformational changes in the Env spike triggers the viral transmembrane protein gp41 to drive the fusion of the viral and cellular membranes, thus leading to the release of the viral core into the target cell cytoplasm (107). This initiates the subsequent series of events of the early phase: reverse transcription, nuclear entry, and integration.

The capsid, by itself or by recruiting cellular cofactors, is being recognized as the master regulator of the early phase of viral replication (108-111). The reverse transcription process- a defining feature of the replication of retroviruses such as HIV, takes place within the confines of the capsid in the cytoplasm, potentially to avoid exposure of the vRNA and/or the vDNA to the innate immune sensors (112-114). Reverse transcription occurs in the context of a ribonucleoprotein complex of vRNA, viral proteins, and host factors- termed reverse transcription complex (RTC). The RT enzyme uses the host cellular tRNALys to prime the reverse transcription of the vRNA into a double-stranded DNA copy (vDNA) containing long terminal repeat (LTR) sequences at the 5’ and 3’ ends (115). Importantly, the tendency of the RT to accommodate transfers of the growing DNA strand between the two copies of the vRNA during the reverse transcription process leads to the generation of recombinant progeny viruses. The capsid-binding cellular cofactor cyclophilin A (CypA) has been demonstrated to promote the viral reverse transcription process in a target cell type-dependent manner (116) (117) . Subsequently, the RTC transitions into another nucleoprotein complex termed pre-integration complex (PIC), and the PIC-resident vDNA LTR ends are bound by the viral IN enzyme molecules (118). The PIC, in concert with capsid and cellular cofactors, orchestrates the nuclear entry and integration of the vDNA into the host chromosome (119-122). As a member of the lentivirus genus of retroviruses, HIV-1 can infect both dividing (activated CD4+ T cells) and non-dividing (macrophages and quiescent T cells) target cells. Because an intact capsid is too big (~60 nm in diameter at the broad end of the cone) to navigate the nuclear pore complex (NPC, ~40 nm in diameter at the central opening) (123), the reverse transcription process was generally considered to be synchronized with the disassembly of the capsid (aka uncoating) in the cytoplasm (124). However, accumulating evidence suggest that uncoating may also occur at the NPC and/or in the nucleoplasm; the latter scenario likely involves capsid and/or NPC remodeling (125) (126). For instance, the capsid-binding host proteins CypA, Nucleoporin 153 (Nup153), Nucleoporin 358 (Nup358), and, more recently, cleavage and polyadenylation specificity factor 6 (CPSF6) have been demonstrated to facilitate the viral nuclear entry (116) (126) (129). Once inside the nucleus, the PIC-resident viral IN, in concert with host factors such as the CA-recruited CPSF6 (130) and the IN-recruited lens epithelium-derived growth factor (LEDGF/p75) (131-133) ,mediates the preferential integration of the vDNA into transcriptionally active gene-dense regions of the human chromosomal DNA (11) (134) (138). The integrated vDNA (provirus) persists for the life of the cell (11). The establishment of the provirus culminates the early phase of HIV replication.

In the late phase of HIV-1 replication, the proviral DNA may be transcribed by the cellular transcriptional machinery or, under certain circumstances, remain silent (latent provirus) (139). After transcription and posttranscriptional processing, the completely spliced viral mRNAs are transported to the cytoplasm by the canonical host exportin 1 (XPO1)-RanGTP nuclear export pathway, whereas the transport of the unspliced full-length and partially spliced viral mRNAs is facilitated by the viral Rev protein in concert with XPO1-RanGTP (140). In the cytoplasm, the viral mRNAs are translated into polyprotein precursors [Pr55Gag, Pr160GagPol, and gp160], regulatory proteins (Rev and Tat), and accessory proteins (Nef, Vif, Vpu, and Vpr). Next, the viral proteins and full-length vRNAs needed for the generation of progeny virus traffic to the virus assembly site (typically, the plasma membrane) where the Gag protein binds to the membrane via its MA domain, dimerizes via it CA domain, and coordinates the assembly of an immature virus particle bound by the cell membrane (141-143). The Gag NC domain binds to the packaging signal () sequence of two copies of full-length vRNA and ensures their packaging into assembling virus particle. The cell membrane enclosing the nascent virus particle is embedded with trimeric complexes of non-covalently linked heterodimers of the viral gp120 and gp41 proteins that are derived from the viral gp160 protein by the action of cellular endopeptidases(144). This non-infectious immature virus particle is then released from the producer cell by the action of the Gag p6 domain-recruited cellular endosomal sorting complexes required for transport (ESCRT) machinery. During the concomitant viral maturation process, the viral PR enzyme, itself encoded as part of the Gag-Pol, first matures via auto-processing and subsequently processes the Gag into MA, CA, NC, and p6, and the Gag-Pol into RT and IN, mature functional proteins (145). The resulting mature infectious virus particle is termed virion, the transmission of which, as a cell-free virus particle or via cell-cell contacts, to a new target cell leads to the establishment of a new infection (146) (147).

HIV-1 PATHOGENESIS

HIV-1 transmission at the mucosal membrane- the main portal of virus entry, generally results from a single free or cell-bound virion (transmitted/founder virus) infecting a single target cell (147-150). The current understanding of the earliest events during acute HIV-1 infection in vivo mainly derives from studies involving HIV-1 infection of human tissue explants ex vivo (151), and SIV infection of the non-human primate rhesus macaque (152) (153). A typical time course of HIV-1 infection progresses through 4 phases: eclipse, acute infection, chronic infection, and AIDS (154). The first one or two weeks after the virus transmission mark the eclipse phase during which HIV-1 is actively replicating at the site of infection and spreading to distant susceptible tissues and organs, all without detectable viremia or symptoms or immune response. The first detection of viral RNA in the blood marks the end of the eclipse phase. The acute/primary infection phase (weeks 2-4) is marked by high levels of viremia (>107 copies of viral RNA/mL of blood), large pools of infected CD4+ T cells in blood and lymphoid tissues, and, consequently, acute depletion of CD4+ T cells (155). This phase is also frequently characterized by flu or mononucleosis-like symptoms. Both humoral (antibodies targeting viral proteins) and cell-mediated (CD8+ cytotoxic T cells targeting viral antigen-expressing infected cells) host immune response is initiated at the time of peak viremia (42). Majority of the productively infected CD4+ T cells die from activation-induced cell death (AICD), viral cytopathic effects (CPE), or CTL-mediated cell killing. A significant proportion of non-productively infected resting CD4+ T cells in the susceptible lymphoid tissues have been shown to undergo pyroptosis, a form of programmed cell death. The resulting decline in CD4+ T cell numbers and viremia, arising from the eventual catch-up by the host immune system and the exhaustion of available target cell pool, mark the end of the acute phase. This is followed by the chronic infection phase during which the viremia levels stabilize to a set point, which can vary by orders of magnitude between individuals. The CD4+ T cell levels continue to steadily decrease due to the death of sizeable number of infected cells, and there is chronic immune activation and inflammation. If untreated with ARV, the HIV infection advances to the fourth and final AIDS phase anytime between months to 20 years (10 years on average). The AIDS phase is marked by significantly declining CD4+ T cell numbers and increasing viremia levels; the consequent loss of immune control leads to opportunistic infections, cancers, and, ultimately, to the death of the infected individual (15). The AIDS is generally considered to result from the HIV-infection associated loss of the CD4+ T cells. However, because the turnover rate of SIV-infected cells in natural hosts who do not progress to AIDS is comparable to that of HIV-infected cells in humans who do progress to AIDS in the absence of cART, it has been suggested that the infection-associated CD4+ T cell loss may not be the sole driver of disease progression to AIDS in humans (154). Hence, two characteristics distinguishing HIV-1 infection in humans from SIV infections in their natural hosts, namely the chronic immune activation and the robust infection of diverse subsets of CD4+ T cells, has been postulated to contribute to the development of AIDS in humans, by causing immune exhaustion and depleting immune cells protective against opportunistic infections, respectively (154).

HIV-1 LATENCY

The current cART regimens suppress viral replication, reduce plasma virus levels to below the clinical detection limit (~50 copies of HIV-1 RNA/mL), and prevent disease progression. However, cART does not eliminate proviruses; traces of HIV-1 RNA can still be detected in the plasma by using ultrasensitive assays (37) (156). This is primarily due to HIV-1 establishing a stable reservoir of non-productively infected and long-lived rCD4s (referred to as latent virus reservoir) harboring proviruses, within days of virus transmission and before detectable viremia (2) (35) (157) (158) Notably, only around 2-7% of those proviruses in the rCD4s are replication-competent and thus constitute the relevant or bona fide population of latent reservoir (159); the other predominant population comprises of defective proviruses (43) (159) (161). The latent reservoirs have been shown to be present in different anatomical compartments including the peripheral blood, lymph nodes, gut-associated lymphoid tissue (GALT), and central nervous system (CNS) (162-167), and, besides the CD4+ T cells, other types of immune cells, especially of the myeloid lineage, have also been reported to contribute to the generation and maintenance of the latent reservoirs. However, the rCD4s from the peripheral blood continue to represent the most extensively characterized latent reservoir. These latent virus reservoirs are remarkably stable (168). The resting and memory state of these infected cells largely precludes proviral gene expression and viral protein production [160]. Consequently, these latent virus reservoirs are generally invisible to CTL-mediated host immune response and also immune to cART, thus presenting the greatest barrier to HIV cure. HIV-1 can persist in different subsets of memory T cells including central (TCM), effector (TEM), transitional (TTM), and the stem cell-like memory T cells. However, the TCM cells, which display diverse tissue distribution profile, are generally regarded as the HIV-preferred latent cell reservoirs (169) The latent HIV-1 reservoir, first evidenced in vivo in 1995 (34), displays an extremely slow decay rate (t1/2 = 3.7 years) in PLHIV on cART (168); for instance, natural clearance of a million latently-infected cells may take ~73 years. Preempting the establishment of such latent HIV reservoirs in infected individuals continues to remain a formidable therapeutic challenge.

An early initiation of cART has been shown to minimize the size of this latent viral reservoir but is incapable of preventing its establishment. For instance, initiating the cART very early (3rd day post infection) in the SIV-infected rhesus macaque non-human primate model still did not prevent the establishment of the latent viral reservoirs (170). In the case of HIV-1 infection, initiating cART extremely early during infection (10 days post transmission) led to undetectable virus levels in the infected individual for up to 2 years on cART; however, the virus rebounded 32 weeks after interruption of cART (171). Further, these long-lived latently-infected rCD4s are maintained by homeostatic proliferation, antigen-driven proliferation, and integration site-driven clonal expansion, and thus persist despite long-term cART in PLHIV (169) (172-176). The homeostatic proliferation is mediated by common gamma chain family of cytokines (IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21), the antigen-stimulated proliferation may be mediated by specific antigens (cytomegalovirus, CMV; human papillomavirus, HPV, Epstein-Barr virus, EBV) or non-specific immune activators (bacteria), and the integration site-driven clonal expansion could result from viral integration into cell growth or cell cycle-related genes (177). Especially, recent findings indicate that the clonally-expanded population of the latent reservoir containing replication-competent provirus (178) (179), a fraction of which are transcriptionally active even during cART (180), may account for over 50% of the latent reservoir (172) (181) (182) and are more dynamic that previously anticipated (161) (176).

Despite cART-mediated suppression of ongoing virus replication, transient bursts of virus production from such latently infected cells, potentially upon exposure to antigens or cytokines, may contribute to the residual plasma HIV-1 RNA. Alternatively, ongoing virus replication in tissue compartments ineffectually targeted by, or inaccessible to, CART may also contribute to the residual plasma HIV-1. However, the resident virus populations in such inaccessible tissue compartments evolve differently and thus display reduced diversity than those of the latent HIV reservoirs. Direct cell-to-cell transmission of virus via virological synapses has also been proposed to contribute to the residual ongoing virus replication and establishment of latent HIV reservoir(183) (184). Any disruption of cART will enable resumption of virus production from proviruses in latently-infected cells, thus leading to a relapse of pre-treatment level viremia within days to weeks (37) (39) (185). Hence, an uninterrupted and life-long cART is essential for effectively managing HIV in PLHIV.

If untreated, HIV evades both the humoral and cell-mediated host immune response by acquiring escape mutations in its genome(186-192) and continues to actively replicate in infected individuals throughout their lifetime (193). This discounts any need for HIV to establish latency as a means to persist in infected individuals. The prevalent theory proposed (46) to explain the incidence of HIV-1 latency invokes the transmitted viruses’ preference for CCR5 tropism (150) and, consequently, for activated CD4+ T cells capable of transitioning into rCD4s. The activated CD4+ T cells are marked by the activation-induced upregulation and increased availability of CCR5, completion of the early events of virus replication leading to the critical step of vDNA integration (i.e. establishment of provirus) within few hours post infection, and the ready availability of the cellular factors required for the transcription of the proviral DNA. Conversely, the rCD4s are deficient in the expression or levels of the cellular cofactors required for optimal virus replication; for instance, completion of the reverse transcription process may take up to 3 days in rCD4s. Though the activated CD4+ T cells infected by HIV-1 have a very short half-life (t1/2 of ~1day) and die of one of the many proposed cell death pathways, if HIV-1 stochastically infects activated CD4+ T cells that are in the process of transitioning into memory phenotype (194), a sufficient window of time may be available for completion of the early events of virus replication culminating in the establishment of the provirus. The transition into memory phenotype causes sequestration of host transcription factors that are essential for virus gene expression from the provirus, and the resulting transcriptionally-silent provirus (195) may further be subjected to certain epigenetic modifications that sustain the latent phenotype (158) (196).

Recent reports suggest that HIV-1 can directly infect resting CD4+ T cells (197). Though HIV can enter resting CD4+ T cells (198), certain host restriction factors present significant blocks to steps in the early phase of virus replication. For instance, the host-encoded protein sterile alpha-motif (SAM) and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) (199) (200) is highly expressed in resting CD4+ T cells and impairs viral reverse transcription by limiting the availability of the nucleotides essential for vDNA synthesis(201) (202) . The resulting incomplete vDNA products are sensed by interferon-γ inducible protein 16 (IFI16), which leads to pyroptosis, release of pro-inflammatory cytokines, and ultimately the depletion of CD4+ T cells. Occasionally, HIV infection in some resting CD4+ T cells progresses through reverse transcription and nuclear import of the ensuing vDNA, which may or may not be integrated into the host chromosome. The unintegrated vDNA is typically circularized by end-to-end joining of the viral DNA LTR ends into 2-LTR circles by the host non-homologous end joining (NHEJ) pathway or into 1-LTR circles via homologous recombination (203), and these unintegrated circular forms of vDNA persist for extended periods of time (204). Recent demonstration of cellular activation-induced and IN-dependent linearization of the 2-LTR circles and their subsequent integration into host chromosome suggests that the 2-LTR circles may also serve as a reserve supply for integration-competent vDNA. Taken together, the generation and maintenance of a reservoir of rCD4s, which are not, or poorly, targeted by CTLs and cART represent a major hurdle to HIV cure efforts (174).

HIV-1 CURE

Two pathways have been proposed for achieving cART-free HIV cure: sterilizing cure and functional cure (46) (205). The “sterilizing cure” refers to complete elimination of HIV from the patient’s body by purging the latent reservoirs of replication-competent proviruses. The “functional cure” aims for immune system-mediated durable suppression of viral replication, in the absence of cART and without completely eliminating replication-competent HIV (206).

Two prominent clinical cases highlight the tantalizing prospect that HIV can be eliminated (Berlin patient) or temporarily controlled in the absence of cART (Mississippi baby). In 2006, an HIV-1-positive patient maintaining a cART-induced virologic suppression for over 10 years was diagnosed with acute myeloid leukemia that was neither associated with the HIV infection nor the treatment. This individual, later named Berlin patient, first underwent myeloablative conditioning regimen that employs chemotherapy and whole-body radiation to eliminate the host stem and immune cells. Subsequently, the patient received allogeneic hematopoietic stem cell transplantations (HSCT) from a chosen donor who carried a homozygous deletion in the CCR5 gene that codes for the namesake co-receptor required for HIV entry. Following discontinuation of cART, neither viral RNA in the peripheral blood nor replication-competent proviral DNA in tissue compartments have been detected over the past 12 years (207) (208). Though the underlying mechanism(s) remain unclear, three likely contributing factors include the conditioning regimen and the graft-versus-host disease (GvHD), both of which enabled the elimination of HIV-infected cells, and the non-permissiveness of the transplanted cells to new HIV infections. However, the inherent and significant risks associated with this clinical procedure makes it unsuitable for PLHIV who are negative for myeloid malignant diseases. Further, CXCR4-tropic HIV variants pre-existing in patients who receive such allogeneic transplantation with CCR5 Δ32 homozygous stem cells can breakthrough and rebound under the selection pressure (209). The Mississippi baby was born in 2010 to an untreated HIV-1-infected mother and was started on cART 30 hours after birth. The baby tested positive for HIV up to 3 weeks of age but then the virus declined to below detectable levels by the end of 4 weeks of age. Despite the discontinuation of cART at 18 months of age, the virologic suppression was maintained (210). However, the child experienced virologic rebound in mid 2014, and the child was placed back on cART (211). Accumulating evidence over the years have substantiated the significant role of initiating the cART as early as feasible during the early stages of infection in containing the establishment of latent HIV reservoirs and achieving long-lasting remission in the absence of cART (212) (213); however, the case of the Mississippi baby highlights certain limitations of this strategy. Research directed towards translating the insights gained from these clinical cases into viable curative interventions targeted at achieving cART-free remission in PLHIV are currently underway.

The mainstay of the therapeutic strategies focused on eliminating the latent virus reservoir is the kick(shock)-and-kill strategy (214-217) that relies on the use of latency reversing agents (LRAs) to induce de novo production of viral proteins from the replication-competent proviruses in the latently-infected rCD4s, followed by viral cytopathic effect-induced or HIV-specific CTL-induced cell death [46, 218]. However, recent evidence suggests that the LRA-treated cells may not be cleared by cytopathic effects (218). Hence, the first, and the most critical step, in CTL response after latency reversal is a prompt and effective recognition of the viral antigens produced from the replication-competent proviruses (42). In vivo, CTLs face multiple roadblocks to recognition of latently-infected cells. Recent evidence suggests that, unlike in the case of HIV-infected individuals who initiated cART during acute infection, almost all the replication-competent and defective proviruses from the rCD4s in patients who started cART during chronic infection contained escape mutations in certain dominant viral epitopes targeted by CTLs, and thereby are unaffected by CTL response (187). These CTL escape mutations arise early in infection due to robust CTL response in the absence of cART and hence are archived in the latent reservoir. This necessitates the latent reservoir-targeting CTL-based therapies to be directed towards subdominant viral epitopes for which the virus hasn’t acquired any escape mutations.

In HIV-infected individuals, 300 out of every 1 million rCD4s harbor a provirus (219); nevertheless, only one among those contain an inducible replication-competent provirus, whereas the remaining rCD4s harbor defective proviruses (168) (220). Irrespective of whether the cART is initiated during the acute infection or chronic infection phase, majority (over 90%) of the proviruses are defective (159). Early initiation of ART limits the size of the reservoir but does not profoundly affect the proviral landscape (221). The primary determinant of the viral IN binding to, and mediating the chromosomal integration of, the vDNA is the specific affinity between the viral enzyme and intact LTR ends of the vDNA. This permits indiscriminate integration of full-length, internally-deleted, and defective viral DNAs into host chromosome. The predominance of defective proviruses in latent reservoirs is an outcome of apolipoprotein B editing complex 3G (APOBEC3G)-induced hypermutations, inactivating point mutations, packaging signal () deletions, major splice donor mutations, and large internal deletions (43) (159). However, defective proviruses have been shown to be transcribed into RNAs that are spliced and translated (222). More importantly, some CTL-targeted epitopes are produced, despite the presence of upstream lethal mutations, through aberrant translation, and such cells are recognized by HIV-specific CTLs. Because of the predominance of defective proviruses over replication-competent proviruses, the effectiveness of the CTL response can be significantly blunted by the non-productive targeting of cells harboring defective proviruses (223).

Contrary to the promising results from studies based on in vitro latency model systems, multiple clinical trials testing strategies based on the kick-and-kill approach have consistently failed to shrink, let alone eliminate, the latent viral reservoirs (224). Insufficient latency reversal and suboptimal immune clearance have been frequently ascribed to such disappointing clinical outcomes. Accordingly, recent findings implicate additional barriers, present in vivo but absent in the in vitro latency models, in the inefficient CTL-mediated elimination in vivo. Apparently, the latency models do not fully recapitulate the complex nature of the latent virus reservoirs that are established in vivo over several years or decades in the face of cART (225) (226). Nevertheless, and notably, the outcome of the sterilizing or functional curative strategies will likely depend on an effective HIV-specific CTL response- to eliminate any reactivated latently-infected rCD4s or to durably control the viremia, respectively.

HIV-1-SPECIFIC CTL RESPONSE

HIV-1-specific CTLs mount the most critical host immune response towards limiting virus replication and spread during primary HIV infection (155) (186) (229-231). The CTLs, via their T cell receptors (TCR), specifically recognize and bind to short HIV-derived peptides, which are derived from proteasomal processing of mature viral proteins (232) or truncated defective viral proteins, and presented by HLA class I molecules on the surface of the infected cells. Following this direct cell-to-cell contact, an immunological synapse is established between the two cell types that activates a cascade of effector mechanisms targeting the infected cell (233). These include the secretion of cell death-inducing effector molecules like granzymes, perforin, and Fas-ligand, and the release of a variety of antiviral cytokines and chemokines, which collectively orchestrate the killing of the infected cell, potentially before the biogenesis of progeny virus (234). The significance of the CTL-mediated antiviral response to HIV-1 infection is evident from the (1) inverse correlation between the magnitude and promptness of the HIV-specific CTL response and the viral load set point during acute HIV infection, (2) rapid evolution of escape mutations within the sequences encoding the viral epitopes targeted by the CTLs, (3) robust ability of HIV-specific CTLs from infected individuals to kill HIV-infected cells in vitro (235), and (4) increase in viremia upon depletion of CTLs during acute SIV infection in the non-human primate animal model macaque (236). Further, the strong selective pressure exerted on the virus to escape the CTL response, both at the individual and population level, is a major driver of HIV evolution (237-239). The HIV-specific CTLs have also been reported to control HIV infection via non-cytotoxic mechanisms, especially by secreting beta-chemokines that block the HIV infection of target cells (240).

Despite the protective role played by CTLs during acute HIV infection, CTL response eventually fails to durably control virus replication and prevent disease progression in untreated HIV-infected individuals (241) (242). This has been attributed to the virus acquiring CTL-resistant escape mutations (243) (244), virus disrupting the HLA Class I-mediated antigen presentation pathway (245), dysfunction of the CD8+ T cells (246), and the rapid establishment and compartmentalization of non-replicating proviruses in rCD4s (latent virus reservoir) during primary HIV infection (42) (247) . The CTL-countering escape mutations acquired by the virus may interfere with processing of viral epitope, loading of viral epitopes onto HLA molecules, and binding of viral epitope antigens to TCR(243) (248). Although several mother-to-child and adult transmission studies have demonstrated that the CTL escape mutant viruses are transmitted (239) (249-251), WT viruses are preferentially transmitted when an HIV-infected individual harbors a mixture of wild-type (WT) and CTL-resistant mutant viruses (252). This suggests that the CTL-escape mutations may impose a significant fitness cost on the viral variants. In untreated PLHIV, persistent exposure to HIV antigens (chronic antigenic stimulation) causes progressive dysfunction of the CD8+ T cells, termed T cell exhaustion. This is marked by diminished proficiency of antigen-induced proliferation, reduced polyfunctionality, and apoptosis. The exhausted CD8+ T cells also express a variety of coinhibitory molecules- the programmed cell death-1 (PD-1) being the central player (253) (254), which further impair their antiviral activity. Nevertheless, long-term cART has been reported to partially relieve the manifestations associated with T cell exhaustion. The proviruses in the latently-infected rCD4s are deemed transcriptionally silent and, consequently, lacking in viral antigen production- a prerequisite for CTL-mediated recognition and cell killing. This potentially renders the latently-infected rCD4s impervious to CTL-mediated host immune responses. However, because the CTLs are capable of recognizing even a single HLA-peptide antigen complex displayed on cell surface, an escape from CTLs would require the maintenance of a remarkably rigorous state of latency over a period of many years in cART-experienced individuals. Yet, available evidence indicates that episodic activation of a subset of such latently-infected cells may lead to low-level transient expression of HIV antigens (174). Therefore, latency has been proposed to be the principle but not the exclusive barrier to CTL-mediated clearance of HIV-infected cells. Conversely, a role for CTL in limiting the expansion of viral reservoir in HIV-infected individuals on cART has been proposed. For instance, in SIV-infected macaques on cART, depletion of CD8+ T-cells was shown to stimulate the levels of SIV transcripts, thus implicating a role for CD8+ T-cells in suppressing viral transcription (255). Recent research raises the possibility that the replication-competent proviruses in latent cells may be inherently resistant to CTL response (256). For instance, treatment of CD4+ T cells from HIV-infected individuals on cART with combinations of LRAs and autologous CTLs diminished the levels of the cell-associated HIV DNA but not the replication-competent provirus. Importantly, this failing appears to neither stem from immune escape by the virus nor dysfunction of the autologous CTLs, because CD4+ T cells inoculated with autologous reservoir virus were eliminated by the autologous CD8+ T cells.

The replication strategy employed by HIV-1 is generally considered tuned towards ensuring the establishment of the provirus before the infected cell becomes the target of CTL response. This is because the incoming vRNA is not translated and the production of viral proteins, which are the de facto precursors for the peptide antigens targeted by CTL, requires transcription of viral mRNAs from the chromosomally-integrated provirus. However, studies in SIV-infected rhesus macaques demonstrated that the early presentation of peptide epitopes processed from the incoming viral Gag protein leads to the recognition of the target cell by the Gag-specific CTLs even before proviral DNA integration (257)In the case of HIV-1 infection in activated CD4+ T cells, peptide epitopes derived from the incoming viral proteins and presented by protective HLA alleles have been reported to be recognized by HIV-specific CTLs and to confer antiviral activity (258) (259). Notably, HIV-specific CTLs from HCs have been shown to be significantly efficient in recognizing and eliminating target CD4+ T cells even before the establishment of a productive infection (260) (261)

HIV-1 CONTROLLERS

A key impetus for the ongoing research focused on a functional cure for HIV is the recognition of HCs- a subgroup of untreated HIV-infected individuals with clinically undetectable viremia (50 RNA copies/mL plasma) and normal or elevated CD4+ T cell counts (median levels at >500 cells per cubic millimeter of blood) for extended periods of time (many years to decades) (47) (48) . The HCs comprise 1% of untreated PLHIV, and majority of them do not progress to AIDS. Though uncommon, some HCs may eventually lose the virus control. The cART-naïve HCs differ from the post-treatment controllers (PTC)- another subgroup of PLHIV who exhibit sustained virologic control after discontinuing cART (262). Because HIV infection in cART-naïve HCs is marked by durable suppression of viral replication, disease progression, and viral transmission, they are considered an apt model for identifying and defining the molecular mechanisms underlying these protective immunologic traits, which may significantly advance the research on HIV cure (263).

The HCs exhibit distinct genetic and immunologic characteristics, and several distinct mechanisms have been proposed to explain the HC phenotype (264). However, robust HIV-1-specific CTL responses have been reported to be a major player and, many times, a common determinant in the manifestation of the HC phenotype(242) (265-268). It has been suggested that a distinct host response, likely during early in infection, plays a major role in conferring the HC phenotype. Accordingly, the HIV set point- the stabilized viral load following acute infection that is considered a predictive marker for disease progression, generally correlates with the magnitude of the HIV-specific CTL response (188). However, because sampling in HIV-infected individuals is typically after peak viremia, the current understanding of acute HIV infection dynamics is imprecise.Though the contribution of the HIV genetic variation- especially in the context of the viral accessory genes, to the HC phenotype has been studied extensively, the findings have been largely variable and many of the proposed models await verification (269). This has led to the proposal that the host factors might play a relatively major role in conferring the robust and sustained virus control in HCs (270).

Polymorphism within the HLA class I locus has been reported to constitute the primary host genetic determinant of HIV infection outcome (271). Certain HLA alleles associated with control of HIV-1 and non-progression to AIDS (e.g. HLA-B*27, HLA-B*57) are prevalent in HCs, whereas HLA alleles associated with accelerated disease progression (e.g. HLA-B*35) are scarce in HCs (264) (272) (273). Conversely, some PTC cohorts are marked by low incidence of the protective HLA-B*27 and HLA-B*57 alleles, and higher prevalence of HLA-B*35 allele. This suggests that the HC’s ability to robustly control HIV-1 may be largely dependent on potent HLA-B-restricted HIV-specific CTLs. Interestingly, a proportion of macaques carrying MHC class I allele Mamu-B*08 or Mamu-B*17, the viral antigen-binding motifs of which resemble those of the human HLA-B*27 or HLA-B*57, respectively [(274) (275) , have been shown to display HC-like phenotype when infected with pathogenic SIV (276-278). The HIV-specific CTLs in HCs are functionally superior to that in PTCs and CPs- in terms of avidity and polyfunctionality, in countering virus replication, and thus lead to better immunologic control (279-281). Further, unlike the HIV-specific CTLs in CPs, the HIV-specific CTLs in HCs mediate a sustained response (282) (283) because they are more resistant to the persistent antigen stimulation-induced T-cell exhaustion (284), and do not lose the proliferative capacity (285) during the chronic infection phase because they are better at evading the inhibitory effect of the regulatory T cells (Treg) (286). The HIV-specific CTLs from HCs are also more inhibitory to HIV-1 replication in vitro (287).

 

The protective HLA alleles have been reported to be distinctive in their propensity to present the most conserved viral epitopes to the HIV-specific CTLs (288). The resulting immune pressure on the virus drives the emergence of escape mutations within the sequences that encode the CTL-restricted viral epitopes, which may consequently be impaired in processing, loading onto the HLA molecules, and binding to the TCR on CTLs. However, the evolution of the escape mutations in the most conserved regions of the HIV-1 genome invariably imposes significant fitness costs on the mutant viral variants (289). Therefore, though the generation of viral variants may appear to have compromised the protective role of HLA alleles, the ensuing negative impact on the viral replication efficiency has been proposed to confer the characteristic immune control in HCs harboring such protective HLA alleles. Accordingly, the influence of the HLA loci on set point viremia in HIV-infected individuals is primarily mediated through its immune pressure on viral genetic variants, as evidenced from the exclusive association of HLA variants with specific viral mutants (290) (291).

Some of the most immunodominant viral epitopes targeted by CTL are derived from the viral Gag and Env proteins. Gag-specific CTLs have been shown to be more potent in viral suppression than the Env-specific CTLs (292), and, accordingly, robust CTL-mediated targeting of Gag epitopes has been associated with lower viral set point and, consequently, slower disease progression (268) (293). For instance, the slower progression to AIDS by HLA-B*27:05-positive HIV-infected individuals has been ascribed to the CTL response toward the HLA-B*27-restricted immunodominant Gag epitope KK10 (294-296). When viral variants harboring escape mutations (that compromise the CTL response) within the KK10 epitope and compensatory mutations (that relieve the viral fitness cost) arise, typically late in infection, it leads to rapid progression to AIDS (188) (297). Interestingly, the human anti-HIV restriction factor tripartite motif-containing protein 5 alpha (huTRIM5), which binds to the incoming viral capsid core and inhibits the viral reverse transcription, has been implicated in the control of HIV infection in HCs carrying the HLA-B*27 or HLA-B*57 alleles; the CTL escape HIV-1 CA mutants exhibited enhanced sensitivity to the restriction by the human huTRIM5 (298-300). A direct comparison of the functional characteristics of the HLA-B*27-KK10-specific TCRs from the HCs and CPs indicated that the TCRs did not contribute to the differential CTL response in these two populations [301]. Further, the latent viruses in patients who initiate cART during the chronic phase of infection contain escape mutations in CTL-targeted dominant viral epitopes and thus are immune to respective CTLs (187). Recent immune-based therapeutic studies have provided prospective evidence that CTL responses, especially those targeting the subdominant viral epitopes that hasn’t acquired any CTL escape mutations (18), may play a critical role in HIV cure. Rhesus macaques vaccinated with a replicating CMV vector expressing SIV genes and then challenged with a pathogenic SIV virus became infected, but the virus was subsequently eliminated in half of the animals. This was attributed to the vaccine-induced generation of virus-specific broad CTL responses that targeted the HLA class 1-restricted subdominant epitopes and not the immunodominant epitopes capable of mutating with ease (302)(303)

Eliminating nonproductively-infected resting CD4+ T cells, i.e. after viral entry but before reverse transcription, can prevent both abortive and latent infection, thereby preempting the CD4+ T cell depletion and the size of the latent virus reservoir, respectively. Interestingly, HIV-specific CTLs have been reported to be capable of recognizing cognate peptides derived directly from the incoming virus particles and presented via the HLA Class I molecules, both in activated CD4+ T cells (258) (259) and in resting CD4+ T cells (260). More recently, incoming HIV-1 particles in resting non-productively infected CD4+ T cells were reported to be processed by host proteasomes and aminopeptidases into antigens that are then displayed by the HLA-I molecules on the cell surface. Strikingly, HIV-specific CTLs from the HCs, but not the CPs, harboring at least one of the two protective HLA class I alleles- HLA-B27 or HLA-B57, were shown to recognize such virus inoculum-derived peptides, form synapses between the two cell types, and orchestrate cell death, all within few hours (261). The identification of factor(s) that enable the CD8+ T cells from HCs, but not the CPs, to better recognize and target the non-activated infected cells may provide promising avenues for not only reducing the viral reservoir but also potentially limit the establishment of the latent virus reservoir via T-cell based prophylactic vaccines.

The recognition of HCs, despite the challenges discussed above, has spurred the hopes of devising sustainable HIV cure strategies. Assembling large cohorts of HCs will significantly aid in identifying and characterizing their unique immune correlates. However, because the clinical outcomes of HCs can be heterogeneous and because the treatment guidelines for HCs are still inexact, it is critical to precisely define the HC phenotype that will serve as suitable model of functional cure research. The recent identification of viral properties and host factors potentially associated with natural loss of virus control in HCs can be used as predictive biomarkers to determine treatment intervention (304-306). Studies on HC cohorts have started to reveal crucial insights on distinctive immune-control mechanisms (261) (307-309) (298-300), including the observation that sustained virus suppression can be attained even in patients lacking the known protective HLA alleles. Therefore, the HCs may hold the key for immunotherapy-based HIV cure (272).


ACKNOWLEDGEMENTS

We acknowledge the support of National Institutes of Health (NIH) grants AI22960, GM082251, DA024558, DA30896, DA033892, and DA021471. We also acknowledge RCMI grant G12MD007586, Vanderbilt CTSA grant UL1RR024975, Meharry Translational Research Center (MeTRC) CTSA grant (U54 RR026140 from NCRR/NIH, Tennessee Center for AIDS Research grant P30 AI110527, and U54 grant MD007593 from NIh. MHD/NIH.

The authors declare no competing financial and nonfinancial interests.

References

1. Chun, T.W., et al., Effect of interleukin-2 on the pool of latently infected, resting CD4+ T cells in HIV-1-infected patients receiving highly active anti-retroviral therapy. Nat Med, 1999. 5(6): p. 651-5.https://doi.org/10.1038/9498 PMid:10371503

2. Ostrowski, M.A., et al., Both memory and CD45RA+/CD62L+ naive CD4(+) T cells are infected in human immunodeficiency virus type 1-infected individuals. J Virol, 1999. 73(8): p. 6430-5.

3. Brenchley, J.M., et al., T-cell subsets that harbor human immunodeficiency virus (HIV) in vivo: implications for HIV pathogenesis. J Virol, 2004. 78(3): p. 1160-8. https://doi.org/10.1128/JVI.78.3.1160-1168.2004 PMid:14722271 PMCid:PMC321406

4. Sonza, S., et al., Monocytes harbour replication-competent, non-latent HIV-1 in patients on highly active antiretroviral therapy. AIDS, 2001. 15(1): p. 17-22. https://doi.org/10.1097/00002030-200101050-00005 PMid:11192864

5. Le Douce, V., et al., Molecular mechanisms of HIV-1 persistence in the monocyte-macrophage lineage. Retrovirology, 2010. 7: p. 32. https://doi.org/10.1186/1742-4690-7-32 PMid:20380694 PMCid:PMC2873506

6. Koppensteiner, H., R. Brack-Werner, and M. Schindler, Macrophages and their relevance in Human Immunodeficiency Virus Type I infection. Retrovirology, 2012. 9: p. 82. https://doi.org/10.1186/1742-4690-9-82 PMid:23035819 PMCid:PMC3484033

7. Sattentau, Q.J. and M. Stevenson, Macrophages and HIV-1: An Unhealthy Constellation. Cell Host Microbe, 2016. 19(3): p. 304-10. https://doi.org/10.1016/j.chom.2016.02.013 PMid:26962941 PMCid:PMC5453177

8. Spiegel, H., et al., Follicular dendritic cells are a major reservoir for human immunodeficiency virus type 1 in lymphoid tissues facilitating infection of CD4+ T-helper cells. Am J Pathol, 1992. 140(1): p. 15-22

9. Smith, B.A., et al., Persistence of infectious HIV on follicular dendritic cells. J Immunol, 2001. 166(1): p. 690-6. https://doi.org/10.4049/jimmunol.166.1.690 PMid:11123354

10. Wu, L. and V.N. KewalRamani, Dendritic-cell interactions with HIV: infection and viral dissemination. Nat Rev Immunol, 2006. 6(11): p. 859-68. https://doi.org/10.1038/nri1960 PMid:17063186 PMCid:PMC1796806

11. Craigie, R. and F.D. Bushman, HIV DNA integration. Cold Spring Harb Perspect Med, 2012. 2(7): p. a006890. https://doi.org/10.1101/cshperspect.a006890 PMid:22762018 PMCid:PMC3385939

12. Ho, D.D., et al., Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature, 1995. 373(6510): p. 123-6. https://doi.org/10.1038/373123a0 PMid:7816094

13. Wei, X., et al., Viral dynamics in human immunodeficiency virus type 1 infection. Nature, 1995. 373(6510): p. 117-22. https://doi.org/10.1038/373117a0 PMid:7529365

14. Perelson, A.S., et al., HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science, 1996. 271(5255): p. 1582-6. https://doi.org/10.1126/science.271.5255.1582 PMid:8599114

15. Lackner, A.A., M.M. Lederman, and B. Rodriguez, HIV pathogenesis: the host. Cold Spring Harb Perspect Med, 2012. 2(9): p. a007005. https://doi.org/10.1101/cshperspect.a007005 PMid:22951442 PMCid:PMC3426821

16. Sharp, P.M. and B.H. Hahn, Origins of HIV and the AIDS pandemic. Cold Spring Harb Perspect Med, 2011. 1(1): p. a006841. https://doi.org/10.1101/cshperspect.a006841 PMid:22229120 PMCid:PMC3234451

17. Campbell-Yesufu, O.T. and R.T. Gandhi, Update on human immunodeficiency virus (HIV)-2 infection. Clin Infect Dis, 2011. 52(6): p. 780-7. https://doi.org/10.1093/cid/ciq248 PMid:21367732 PMCid:PMC3106263

18. Picker, L.J., S.G. Hansen, and J.D. Lifson, New paradigms for HIV/AIDS vaccine development. Annu Rev Med, 2012. 63: p. 95-111. https://doi.org/10.1146/annurev-med-042010-085643 PMid:21942424 PMCid:PMC3368276

19. Stephenson, K.E., H.T. D'Couto, and D.H. Barouch, New concepts in HIV-1 vaccine development. Curr Opin Immunol, 2016. 41: p. 39-46. https://doi.org/10.1016/j.coi.2016.05.011 PMid:27268856 PMCid:PMC4992607

20. Haynes, B.F. and D.R. Burton, Developing an HIV vaccine. Science, 2017. 355(6330): p. 1129-1130.https://doi.org/10.1126/science.aan0662 PMid:28302812 PMCid:PMC5569908

21. Arts, E.J. and D.J. Hazuda, HIV-1 antiretroviral drug therapy. Cold Spring Harb Perspect Med, 2012. 2(4): p. a007161. https://doi.org/10.1101/cshperspect.a007161 PMid:22474613 PMCid:PMC3312400

22. Coffin, J.M., HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science, 1995. 267(5197): p. 483-9. https://doi.org/10.1126/science.7824947 PMid:7824947

23. Collier, A.C., et al., Combination therapy with zidovudine, didanosine and saquinavir. Antiviral Res, 1996. 29(1): p. 99. https://doi.org/10.1016/0166-3542(95)00928-0

24. Collier, A.C., et al., Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine. AIDS Clinical Trials Group. N Engl J Med, 1996. 334(16): p. 1011-7. https://doi.org/10.1056/NEJM199604183341602 PMid:8598838

25. D'Aquila, R.T., et al., Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection. A randomized, double-blind, placebo-controlled trial. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group Protocol 241 Investigators. Ann Intern Med, 1996. 124(12): p. 1019-30. https://doi.org/10.7326/0003-4819-124-12-199606150-00001 PMid:8633815

26. Perelson, A.S., et al., Decay characteristics of HIV-1-infected compartments during combination therapy. Nature, 1997. 387(6629): p. 188-91. https://doi.org/10.1038/387188a0 PMid:9144290

27. Staszewski, S., et al., Safety and efficacy of lamivudine-zidovudine combination therapy in zidovudine-experienced patients. A randomized controlled comparison with zidovudine monotherapy. Lamivudine European HIV Working Group. JAMA, 1996. 276(2): p. 111-7. https://doi.org/10.1001/jama.1996.03540020033026 https://doi.org/10.1001/jama.276.2.111 PMid:8656502

28. Mansky, L.M. and H.M. Temin, Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase. J Virol, 1995. 69(8): p. 5087-94.

29. O'Neil, P.K., et al., Mutational analysis of HIV-1 long terminal repeats to explore the relative contribution of reverse transcriptase and RNA polymerase II to viral mutagenesis. J Biol Chem, 2002. 277(41): p. 38053-61. https://doi.org/10.1074/jbc.M204774200 PMid:12151398

30. Abram, M.E., et al., Nature, position, and frequency of mutations made in a single cycle of HIV-1 replication. J Virol, 2010. 84(19): p. 9864-78. https://doi.org/10.1128/JVI.00915-10 PMid:20660205 PMCid:PMC2937799

31. Autran, B., et al., Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science, 1997. 277(5322): p. 112-6. https://doi.org/10.1126/science.277.5322.112 PMid:9204894

32. Komanduri, K.V., et al., Restoration of cytomegalovirus-specific CD4+ T-lymphocyte responses after ganciclovir and highly active antiretroviral therapy in individuals infected with HIV-1. Nat Med, 1998. 4(8): p. 953-6. https://doi.org/10.1038/nm0898-953 PMid:9701250

33. Lederman, M.M., et al., Immunologic responses associated with 12 weeks of combination antiretroviral therapy consisting of zidovudine, lamivudine, and ritonavir: results of AIDS Clinical Trials Group Protocol 315. J Infect Dis, 1998. 178(1): p. 70-9. https://doi.org/10.1086/515591 PMid:9652425

34. Chun, T.W., et al., In vivo fate of HIV-1-infected T cells: quantitative analysis of the transition to stable latency. Nat Med, 1995. 1(12): p. 1284-90. https://doi.org/10.1038/nm1295-1284 PMid:7489410

35. Chun, T.W., et al., Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature, 1997. 387(6629): p. 183-8. https://doi.org/10.1038/387183a0 PMid:9144289

36. Finzi, D., et al., Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science, 1997. 278(5341): p. 1295-300. https://doi.org/10.1126/science.278.5341.1295 PMid:9360927

37. Wong, J.K., et al., Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science, 1997. 278(5341): p. 1291-5. https://doi.org/10.1126/science.278.5341.1291 PMid:9360926

38. Finzi, D., et al., Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med, 1999. 5(5): p. 512-7. https://doi.org/10.1038/8394 PMid:10229227

39. Davey, R.T., Jr., et al., HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proc Natl Acad Sci U S A, 1999. 96(26): p. 15109-14. https://doi.org/10.1073/pnas.96.26.15109 PMid:10611346 PMCid:PMC24781

40. Blankson, J.N., D. Persaud, and R.F. Siliciano, The challenge of viral reservoirs in HIV-1 infection. Annu Rev Med, 2002. 53: p. 557-93. https://doi.org/10.1146/annurev.med.53.082901.104024 PMid:11818490

41. Warren, J.A., G. Clutton, and N. Goonetilleke, Harnessing CD8(+) T Cells Under HIV Antiretroviral Therapy. Front Immunol, 2019. 10: p. 291. https://doi.org/10.3389/fimmu.2019.00291 PMid:30863403 PMCid:PMC6400228

42. Jones, R.B. and B.D. Walker, HIV-specific CD8(+) T cells and HIV eradication. J Clin Invest, 2016. 126(2): p. 455-63. https://doi.org/10.1172/JCI80566 PMid:26731469 PMCid:PMC4731167

43. Ho, Y.C., et al., Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell, 2013. 155(3): p. 540-51. https://doi.org/10.1016/j.cell.2013.09.020 PMid:24243014 PMCid:PMC3896327

44. Gardner, E.M., et al., The spectrum of engagement in HIV care and its relevance to test-and-treat strategies for prevention of HIV infection. Clin Infect Dis, 2011. 52(6): p. 793-800. https://doi.org/10.1093/cid/ciq243 PMid:21367734 PMCid:PMC3106261

45. Medland, N.A., et al., The HIV care cascade: a systematic review of data sources, methodology and comparability. J Int AIDS Soc, 2015. 18: p. 20634. https://doi.org/10.7448/IAS.18.1.20634 PMid:26626715 PMCid:PMC4666907

46. Siliciano, J.D. and R.F. Siliciano, Recent developments in the effort to cure HIV infection: going beyond N = 1. J Clin Invest, 2016. 126(2): p. 409-14. https://doi.org/10.1172/JCI86047 PMid:26829622 PMCid:PMC4731192

47. Deeks, S.G. and B.D. Walker, Human immunodeficiency virus controllers: mechanisms of durable virus control in the absence of antiretroviral therapy. Immunity, 2007. 27(3): p. 406-16. https://doi.org/10.1016/j.immuni.2007.08.010 PMid:17892849

48. Pereyra, F., et al., Genetic and immunologic heterogeneity among persons who control HIV infection in the absence of therapy. J Infect Dis, 2008. 197(4): p. 563-71. https://doi.org/10.1086/526786 PMid:18275276

49. Bell, S.M. and T. Bedford, Modern-day SIV viral diversity generated by extensive recombination and cross-species transmission. PLoS Pathog, 2017. 13(7): p. e1006466. https://doi.org/10.1371/journal.ppat.1006466 PMid:28672035 PMCid:PMC5510905

50. Hahn, B.H., et al., AIDS as a zoonosis: scientific and public health implications. Science, 2000. 287(5453): p. 607-14. https://doi.org/10.1126/science.287.5453.607 PMid:10649986

51. Lessells, R.J., D.K. Katzenstein, and T. de Oliveira, Are subtype differences important in HIV drug resistance? Curr Opin Virol, 2012. 2(5): p. 636-43. https://doi.org/10.1016/j.coviro.2012.08.006 PMid:23006584 PMCid:PMC3951383

52. Santoro, M.M. and C.F. Perno, HIV-1 Genetic Variability and Clinical Implications. ISRN Microbiol, 2013. 2013: p. 481314. https://doi.org/10.1155/2013/481314 PMid:23844315 PMCid:PMC3703378

53. Singh, K., et al., Drug resistance in non-B subtype HIV-1: impact of HIV-1 reverse transcriptase inhibitors. Viruses, 2014. 6(9): p. 3535-62. https://doi.org/10.3390/v6093535 PMid:25254383 PMCid:PMC4189038

54. Wainberg, M.A. and B.G. Brenner, The Impact of HIV Genetic Polymorphisms and Subtype Differences on the Occurrence of Resistance to Antiretroviral Drugs. Mol Biol Int, 2012. 2012: p. 256982. https://doi.org/10.1155/2012/256982 PMid:22792462 PMCid:PMC3390109

55. Gottlieb, M.S., et al., Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency. N Engl J Med, 1981. 305(24): p. 1425-31. https://doi.org/10.1056/NEJM198112103052401 PMid:6272109

56. Masur, H., et al., An outbreak of community-acquired Pneumocystis carinii pneumonia: initial manifestation of cellular immune dysfunction. N Engl J Med, 1981. 305(24): p. 1431-8. https://doi.org/10.1056/NEJM198112103052402 PMid:6975437

57. Barre-Sinoussi, F., et al., Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science, 1983. 220(4599): p. 868-71. https://doi.org/10.1126/science.6189183 PMid:6189183

58. Clavel, F., et al., Molecular cloning and polymorphism of the human immune deficiency virus type 2. Nature, 1986. 324(6098): p. 691-5. https://doi.org/10.1038/324691a0 PMid:3025743

59. Guyader, M., et al., Genome organization and transactivation of the human immunodeficiency virus type 2. Nature, 1987. 326(6114): p. 662-9. https://doi.org/10.1038/326662a0 PMid:3031510

60. Hemelaar, J. The origin and diversity of the HIV-1 pandemic. Trends Mol Med.  2012. 18(3): p. 182-92. DOI:10.1016/j.molmed.2011.12.001 PMID:22240486

61. Plantier, J.C., et al., A new human immunodeficiency virus derived from gorillas. Nat Med, 2009. 15(8): p. 871-2. https://doi.org/10.1038/nm.2016 PMid:19648927

62. Robertson, D.L., et al., HIV-1 nomenclature proposal. Science, 2000. 288(5463): p. 55-6. https://doi.org/10.1126/science.288.5463.55d PMid:10766634

63. Vallari, A., et al., Confirmation of putative HIV-1 group P in Cameroon. J Virol, 2011. 85(3): p. 1403-7. https://doi.org/10.1128/JVI.02005-10 PMid:21084486 PMCid:PMC3020498

64. Faria, N.R., et al., HIV epidemiology. The early spread and epidemic ignition of HIV-1 in human populations. Science, 2014. 346(6205): p. 56-61. https://doi.org/10.1126/science.1256739 PMid:25278604 PMCid:PMC4254776

65. Sauter, D. and F. Kirchhoff, Multilayered and versatile inhibition of cellular antiviral factors by HIV and SIV accessory proteins. Cytokine Growth Factor Rev, 2018. 40: p. 3-12. https://doi.org/10.1016/j.cytogfr.2018.02.005 PMid:29526437

66. de Silva, T.I., M. Cotten, and S.L. Rowland-Jones, HIV-2: the forgotten AIDS virus. Trends Microbiol, 2008. 16(12): p. 588-95. https://doi.org/10.1016/j.tim.2008.09.003 PMid:18964021

67. Reeves, J.D. and R.W. Doms, Human immunodeficiency virus type 2. J Gen Virol, 2002. 83(Pt 6): p. 1253-65. https://doi.org/10.1099/0022-1317-83-6-1253 PMid:12029140

68. Ariyoshi, K., et al., Plasma RNA viral load predicts the rate of CD4 T cell decline and death in HIV-2-infected patients in West Africa. AIDS, 2000. 14(4): p. 339-44. https://doi.org/10.1097/00002030-200003100-00006 PMid:10770535

69. De Cock, K.M., et al., Epidemiology and transmission of HIV-2. Why there is no HIV-2 pandemic. JAMA, 1993. 270(17): p. 2083-6. https://doi.org/10.1001/jama.270.17.2083 https://doi.org/10.1001/jama.1993.03510170073033 PMid:8147962

70. Kanki, P.J., et al., Slower heterosexual spread of HIV-2 than HIV-1. Lancet, 1994. 343(8903): p. 943-6. https://doi.org/10.1016/S0140-6736(94)90065-5

71. Marlink, R., Lessons from the second AIDS virus, HIV-2. AIDS, 1996. 10(7): p. 689-99. https://doi.org/10.1097/00002030-199606001-00002 PMid:8805859

72. Marlink, R., et al., Reduced rate of disease development after HIV-2 infection as compared to HIV-1. Science, 1994. 265(5178): p. 1587-90. https://doi.org/10.1126/science.7915856 PMid:7915856

73. Saleh, S., et al., Insight into HIV-2 latency may disclose strategies for a cure for HIV-1 infection. J Virus Erad, 2017. 3(1): p. 7-14.

74. Simon, F., et al., Cellular and plasma viral load in patients infected with HIV-2. AIDS, 1993. 7(11): p. 1411-7. https://doi.org/10.1097/00002030-199311000-00002 PMid:7904166

75. Wilkins, A., et al., The epidemiology of HIV infection in a rural area of Guinea-Bissau. AIDS, 1993. 7(8): p. 1119-22. https://doi.org/10.1097/00002030-199308000-00015 PMid:8397950

76. Esbjornsson, J., et al., Long-term follow-up of HIV-2-related AIDS and mortality in Guinea-Bissau: a prospective open cohort study. Lancet HIV, 2018. https://doi.org/10.1016/S2352-3018(18)30254-6

77. Ganser-Pornillos, B.K., M. Yeager, and O. Pornillos, Assembly and architecture of HIV. Adv Exp Med Biol, 2012. 726: p. 441-65. https://doi.org/10.1007/978-1-4614-0980-9_20 PMid:22297526

78. Zhao, G., et al., Mature HIV-1 capsid structure by cryo-electron microscopy and all-atom molecular dynamics. Nature, 2013. 497(7451): p. 643-6. https://doi.org/10.1038/nature12162 PMid:23719463 PMCid:PMC3729984

79. Engelman, A. and P. Cherepanov, The structural biology of HIV-1: mechanistic and therapeutic insights. Nat Rev Microbiol, 2012. 10(4): p. 279-90.https://doi.org/10.1038/nrmicro2747 PMid:22421880 PMCid:PMC3588166

80. Watts, J.M., et al., Architecture and secondary structure of an entire HIV-1 RNA genome. Nature, 2009. 460(7256): p. 711-6. https://doi.org/10.1038/nature08237 PMid:19661910 PMCid:PMC2724670

81. Perilla, J.R. and A.M. Gronenborn, Molecular Architecture of the Retroviral Capsid. Trends Biochem Sci, 2016. 41(5): p. 410-420. 82. Schiller, J. and B. Chackerian, Why HIV virions have low numbers of envelope spikes: implications for vaccine development. PLoS Pathog, 2014. 10(8): p. e1004254. https://doi.org/10.1371/journal.ppat.1004254 PMid:25101974 PMCid:PMC4125284

83. Ward, A.B. and I.A. Wilson, The HIV-1 envelope glycoprotein structure: nailing down a moving target. Immunol Rev, 2017. 275(1): p. 21-32. https://doi.org/10.1111/imr.12507 PMid:28133813 PMCid:PMC5300090

84. Zhu, P., et al., Distribution and three-dimensional structure of AIDS virus envelope spikes. Nature, 2006. 441(7095): p. 847-52. https://doi.org/10.1038/nature04817 PMid:16728975

85. Dalgleish, A.G., et al., The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature, 1984. 312(5996): p. 763-7. https://doi.org/10.1038/312763a0 PMid:6096719

86. Herschhorn, A., et al., Release of gp120 Restraints Leads to an Entry-Competent Intermediate State of the HIV-1 Envelope Glycoproteins. MBio, 2016. 7(5). https://doi.org/10.1128/mBio.01598-16 PMid:27795397 PMCid:PMC5080382

87. Klatzmann, D., et al., T-lymphocyte T4 molecule behaves as the receptor for human retrovirus LAV. Nature, 1984. 312(5996): p. 767-8. https://doi.org/10.1038/312767a0 PMid:6083454

88. Munro, J.B., et al., Conformational dynamics of single HIV-1 envelope trimers on the surface of native virions. Science, 2014. 346(6210): p. 759-63.https://doi.org/10.1126/science.1254426 PMid:25298114 PMCid:PMC4304640

89. Kwong, P.D., et al., Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature, 1998. 393(6686): p. 648-59. https://doi.org/10.1038/31405 PMid:9641677 PMCid:PMC5629912

90. Liu, J., et al., Molecular architecture of native HIV-1 gp120 trimers. Nature, 2008. 455(7209): p. 109-13. https://doi.org/10.1038/nature07159 PMid:18668044 PMCid:PMC2610422

91. Ozorowski, G., et al., Open and closed structures reveal allostery and pliability in the HIV-1 envelope spike. Nature, 2017. 547(7663): p. 360-363. https://doi.org/10.1038/nature23010 PMid:28700571 PMCid:PMC5538736

92. Sanders, R.W. and J.P. Moore, Native-like Env trimers as a platform for HIV-1 vaccine design. Immunol Rev, 2017. 275(1): p. 161-182. https://doi.org/10.1111/imr.12481 PMid:28133806 PMCid:PMC5299501

93. Stadtmueller, B.M., et al., DEER Spectroscopy Measurements Reveal Multiple Conformations of HIV-1 SOSIP Envelopes that Show Similarities with Envelopes on Native Virions. Immunity, 2018. 49(2): p. 235-246 e4. https://doi.org/10.1016/j.immuni.2018.06.017 PMid:30076100 PMCid:PMC6104740

94. Freed, E.O., HIV-1 replication. Somat Cell Mol Genet, 2001. 26(1-6): p. 13-33. https://doi.org/10.1023/A:1021070512287 PMid:12465460

95. Li, G. and E. De Clercq, HIV Genome-Wide Protein Associations: a Review of 30 Years of Research. Microbiol Mol Biol Rev, 2016. 80(3): p. 679-731. https://doi.org/10.1128/MMBR.00065-15 PMid:27357278 PMCid:PMC4981665

96. Bushman, F.D., et al., Host cell factors in HIV replication: meta-analysis of genome-wide studies. PLoS Pathog, 2009. 5(5): p. e1000437. https://doi.org/10.1371/journal.ppat.1000437 PMid:19478882 PMCid:PMC2682202

97. Malim, M.H. and P.D. Bieniasz, HIV Restriction Factors and Mechanisms of Evasion. Cold Spring Harb Perspect Med, 2012. 2(5): p. a006940. https://doi.org/10.1101/cshperspect.a006940 PMid:22553496 PMCid:PMC3331687

98. Saphire, A.C., et al., Syndecans serve as attachment receptors for human immunodeficiency virus type 1 on macrophages. J Virol, 2001. 75(19): p. 9187-200. https://doi.org/10.1128/JVI.75.19.9187-9200.2001 PMid:11533182 PMCid:PMC114487

99. Arthos, J., et al., HIV-1 envelope protein binds to and signals through integrin alpha4beta7, the gut mucosal homing receptor for peripheral T cells. Nat Immunol, 2008. 9(3): p. 301-9. https://doi.org/10.1038/ni1566 PMid:18264102

100. Cicala, C., et al., The integrin alpha4beta7 forms a complex with cell-surface CD4 and defines a T-cell subset that is highly susceptible to infection by HIV-1. Proc Natl Acad Sci U S A, 2009. 106(49): p. 20877-82. https://doi.org/10.1073/pnas.0911796106 PMid:19933330 PMCid:PMC2780317

101. Geijtenbeek, T.B., et al., DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell, 2000. 100(5): p. 587-97. https://doi.org/10.1016/S0092-8674(00)80694-7

102. Geijtenbeek, T.B., et al., Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Cell, 2000. 100(5): p. 575-85. https://doi.org/10.1016/S0092-8674(00)80693-5

103. Alkhatib, G., C.C. Broder, and E.A. Berger, Cell type-specific fusion cofactors determine human immunodeficiency virus type 1 tropism for T-cell lines versus primary macrophages. J Virol, 1996. 70(8): p. 5487-94.

104. Deng, H., et al., Identification of a major co-receptor for primary isolates of HIV-1. Nature, 1996. 381(6584): p. 661-6. https://doi.org/10.1038/381661a0 PMid:8649511

105. Doranz, B.J., et al., A dual-tropic primary HIV-1 isolate that uses fusin and the beta-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors. Cell, 1996. 85(7): p. 1149-58. https://doi.org/10.1016/S0092-8674(00)81314-8

106. Feng, Y., et al., HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science, 1996. 272(5263): p. 872-7. https://doi.org/10.1126/science.272.5263.872 PMid:8629022

107. Wilen, C.B., J.C. Tilton, and R.W. Doms, HIV: cell binding and entry. Cold Spring Harb Perspect Med, 2012. 2(8). https://doi.org/10.1101/cshperspect.a006866 PMid:22908191 PMCid:PMC3405824

108. Campbell, E.M. and T.J. Hope, HIV-1 capsid: the multifaceted key player in HIV-1 infection. Nat Rev Microbiol, 2015. 13(8): p. 471-83. https://doi.org/10.1038/nrmicro3503 PMid:26179359 PMCid:PMC4876022

109. Fassati, A., Multiple roles of the capsid protein in the early steps of HIV-1 infection. Virus Res, 2012. 170(1-2): p. 15-24. https://doi.org/10.1016/j.virusres.2012.09.012 PMid:23041358

110. Francis, A.C. and G.B. Melikyan, Single HIV-1 Imaging Reveals Progression of Infection through CA-Dependent Steps of Docking at the Nuclear Pore, Uncoating, and Nuclear Transport. Cell Host Microbe, 2018. 23(4): p. 536-548 e6. https://doi.org/10.1016/j.chom.2018.03.009 PMid:29649444 PMCid:PMC5901770

111. Yamashita, M. and A.N. Engelman, Capsid-Dependent Host Factors in HIV-1 Infection. Trends Microbiol, 2017. 25(9): p. 741-755. https://doi.org/10.1016/j.tim.2017.04.004 PMid:28528781 PMCid:PMC5562514

112. Jacques, D.A., et al., HIV-1 uses dynamic capsid pores to import nucleotides and fuel encapsidated DNA synthesis. Nature, 2016. 536(7616): p. 349-53. https://doi.org/10.1038/nature19098 PMid:27509857 PMCid:PMC4998957

113. Rasaiyaah, J., et al., HIV-1 evades innate immune recognition through specific cofactor recruitment. Nature, 2013. 503(7476): p. 402-405. https://doi.org/10.1038/nature12769 PMid:24196705 PMCid:PMC3928559

114. Yan, N., et al., The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1. Nat Immunol, 2010. 11(11): p. 1005-13. https://doi.org/10.1038/ni.1941 PMid:20871604 PMCid:PMC2958248

115. Hu, W.S. and S.H. Hughes, HIV-1 reverse transcription. Cold Spring Harb Perspect Med, 2012. 2(10). https://doi.org/10.1101/cshperspect.a006882 PMid:23028129 PMCid:PMC3475395

116. De Iaco, A. and J. Luban, Cyclophilin A promotes HIV-1 reverse transcription but its effect on transduction correlates best with its effect on nuclear entry of viral cDNA. Retrovirology, 2014. 11: p. 11. https://doi.org/10.1186/1742-4690-11-11 PMid:24479545 PMCid:PMC3916700

117. Sokolskaja, E., D.M. Sayah, and J. Luban, Target cell cyclophilin A modulates human immunodeficiency virus type 1 infectivity. J Virol, 2004. 78(23): p. 12800-8. https://doi.org/10.1128/JVI.78.23.12800-12808.2004 PMid:15542632 PMCid:PMC524981

118. Miller, M.D., C.M. Farnet, and F.D. Bushman, Human immunodeficiency virus type 1 preintegration complexes: studies of organization and composition. J Virol, 1997. 71(7): p. 5382-90.

119. Grandgenett, D.P., et al., Multifunctional facets of retrovirus integrase. World J Biol Chem, 2015. 6(3): p. 83-94. https://doi.org/10.4331/wjbc.v6.i3.83 PMid:26322168 PMCid:PMC4549773

120. Hilditch, L. and G.J. Towers, A model for cofactor use during HIV-1 reverse transcription and nuclear entry. Curr Opin Virol, 2014. 4: p. 32-6. https://doi.org/10.1016/j.coviro.2013.11.003 PMid:24525292 PMCid:PMC3969716

121. Matreyek, K.A. and A. Engelman, Viral and cellular requirements for the nuclear entry of retroviral preintegration nucleoprotein complexes. Viruses, 2013. 5(10): p. 2483-511. https://doi.org/10.3390/v5102483 PMid:24103892 PMCid:PMC3814599

122. Van Maele, B., et al., Cellular co-factors of HIV-1 integration. Trends Biochem Sci, 2006. 31(2): p. 98-105. https://doi.org/10.1016/j.tibs.2005.12.002 PMid:16403635

123. Knockenhauer, K.E. and T.U. Schwartz, The Nuclear Pore Complex as a Flexible and Dynamic Gate. Cell, 2016. 164(6): p. 1162-1171. https://doi.org/10.1016/j.cell.2016.01.034 PMid:26967283 PMCid:PMC4788809

124. Arhel, N., Revisiting HIV-1 uncoating. Retrovirology, 2010. 7: p. 96. https://doi.org/10.1186/1742-4690-7-96 PMid:21083892 PMCid:PMC2998454

125. Ambrose, Z. and C. Aiken, HIV-1 uncoating: connection to nuclear entry and regulation by host proteins. Virology, 2014. 454-455: p. 371-9. https://doi.org/10.1016/j.virol.2014.02.004 PMid:24559861 PMCid:PMC3988234

126. Bejarano, D.A., et al., HIV-1 nuclear import in macrophages is regulated by CPSF6-capsid interactions at the nuclear pore complex. Elife, 2019. 8.https://doi.org/10.7554/eLife.41800 PMid:30672737 PMCid:PMC6400501

127. Buffone, C., et al., Nup153 Unlocks the Nuclear Pore Complex for HIV-1 Nuclear Translocation in Nondividing Cells. J Virol, 2018. 92(19). https://doi.org/10.1128/JVI.00648-18 PMid:29997211 PMCid:PMC6146805

128. Price, A.J., et al., Host cofactors and pharmacologic ligands share an essential interface in HIV-1 capsid that is lost upon disassembly. PLoS Pathog, 2014. 10(10): p. e1004459. https://doi.org/10.1371/journal.ppat.1004459 PMid:25356722 PMCid:PMC4214760

129. Schaller, T., et al., HIV-1 capsid-cyclophilin interactions determine nuclear import pathway, integration targeting and replication efficiency. PLoS Pathog, 2011. 7(12): p. e1002439. https://doi.org/10.1371/journal.ppat.1002439 PMid:22174692 PMCid:PMC3234246

130. Lee, K., et al., Flexible use of nuclear import pathways by HIV-1. Cell Host Microbe, 2010. 7(3): p. 221-33. https://doi.org/10.1016/j.chom.2010.02.007 PMid:20227665 PMCid:PMC2841689

131. Ciuffi, A., et al., A role for LEDGF/p75 in targeting HIV DNA integration. Nat Med, 2005. 11(12): p. 1287-9. https://doi.org/10.1038/nm1329 PMid:16311605

132. Emiliani, S., et al., Integrase mutants defective for interaction with LEDGF/p75 are impaired in chromosome tethering and HIV-1 replication. J Biol Chem, 2005. 280(27): p. 25517-23. https://doi.org/10.1074/jbc.M501378200 PMid:15855167

133. Poeschla, E.M., Integrase, LEDGF/p75 and HIV replication. Cell Mol Life Sci, 2008. 65(9): p. 1403-24. https://doi.org/10.1007/s00018-008-7540-5 PMid:18264802 PMCid:PMC3902792

134. Achuthan, V., et al., Capsid-CPSF6 Interaction Licenses Nuclear HIV-1 Trafficking to Sites of Viral DNA Integration. Cell Host Microbe, 2018. 24(3): p. 392-404 e8. https://doi.org/10.1016/j.chom.2018.08.002 PMid:30173955

135. Burdick, R.C., et al., Dynamics and regulation of nuclear import and nuclear movements of HIV-1 complexes. PLoS Pathog, 2017. 13(8): p. e1006570. https://doi.org/10.1371/journal.ppat.1006570 PMid:28827840 PMCid:PMC5578721

136. Engelman, A.N. and P.K. Singh, Cellular and molecular mechanisms of HIV-1 integration targeting. Cell Mol Life Sci, 2018. 75(14): p. 2491-2507. https://doi.org/10.1007/s00018-018-2772-5 PMid:29417178

137. Rasheedi, S., et al., The Cleavage and Polyadenylation Specificity Factor 6 (CPSF6) Subunit of the Capsid-recruited Pre-messenger RNA Cleavage Factor I (CFIm) Complex Mediates HIV-1 Integration into Genes. J Biol Chem, 2016. 291(22): p. 11809-19. https://doi.org/10.1074/jbc.M116.721647 PMid:26994143 PMCid:PMC4882448

138. Sowd, G.A., et al., A critical role for alternative polyadenylation factor CPSF6 in targeting HIV-1 integration to transcriptionally active chromatin. Proc Natl Acad Sci U S A, 2016. 113(8): p. E1054-63. https://doi.org/10.1073/pnas.1524213113 PMid:26858452 PMCid:PMC4776470

139. Lusic, M. and R.F. Siliciano, Nuclear landscape of HIV-1 infection and integration. Nat Rev Microbiol, 2017. 15(2): p. 69-82. https://doi.org/10.1038/nrmicro.2016.162 PMid:27941817

140. Karn, J. and C.M. Stoltzfus, Transcriptional and posttranscriptional regulation of HIV-1 gene expression. Cold Spring Harb Perspect Med, 2012. 2(2): p. a006916. https://doi.org/10.1101/cshperspect.a006916 PMid:22355797 PMCid:PMC3281586

141. Balasubramaniam, M. and E.O. Freed, New insights into HIV assembly and trafficking. Physiology (Bethesda), 2011. 26(4): p. 236-51. https://doi.org/10.1152/physiol.00051.2010 PMid:21841072 PMCid:PMC3467973

142. Briggs, J.A., et al., Structure and assembly of immature HIV. Proc Natl Acad Sci U S A, 2009. 106(27): p. 11090-5. https://doi.org/10.1073/pnas.0903535106 PMid:19549863 PMCid:PMC2700151

143. Sundquist, W.I. and H.G. Krausslich, HIV-1 assembly, budding, and maturation. Cold Spring Harb Perspect Med, 2012. 2(7): p. a006924. https://doi.org/10.1101/cshperspect.a006924 PMid:22762019 PMCid:PMC3385941

144. Checkley, M.A., B.G. Luttge, and E.O. Freed, HIV-1 envelope glycoprotein biosynthesis, trafficking, and incorporation. J Mol Biol, 2011. 410(4): p. 582-608. https://doi.org/10.1016/j.jmb.2011.04.042 PMid:21762802 PMCid:PMC3139147

145. Freed, E.O., HIV-1 assembly, release and maturation. Nat Rev Microbiol, 2015. 13(8): p. 484-96. https://doi.org/10.1038/nrmicro3490 PMid:26119571

146. Fackler, O.T., et al., Adding new dimensions: towards an integrative understanding of HIV-1 spread. Nat Rev Microbiol, 2014. 12(8): p. 563-74. https://doi.org/10.1038/nrmicro3309 PMid:25029025 PMCid:PMC5687059

147. Shaw, G.M. and E. Hunter, HIV transmission. Cold Spring Harb Perspect Med, 2012. 2(11). https://doi.org/10.1101/cshperspect.a006965 PMid:23043157 PMCid:PMC3543106

148. Abrahams, M.R., et al., Quantitating the multiplicity of infection with human immunodeficiency virus type 1 subtype C reveals a non-poisson distribution of transmitted variants. J Virol, 2009. 83(8): p. 3556-67. https://doi.org/10.1128/JVI.02132-08 PMid:19193811 PMCid:PMC2663249

149. Derdeyn, C.A., et al., Envelope-constrained neutralization-sensitive HIV-1 after heterosexual transmission. Science, 2004. 303(5666): p. 2019-22. https://doi.org/10.1126/science.1093137 PMid:15044802

150. Keele, B.F., et al., Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc Natl Acad Sci U S A, 2008. 105(21): p. 7552-7. https://doi.org/10.1073/pnas.0802203105 PMid:18490657 PMCid:PMC2387184

151. Veazey, R.S., et al., Protection of macaques from vaginal SHIV challenge by vaginally delivered inhibitors of virus-cell fusion. Nature, 2005. 438(7064): p. 99-102. https://doi.org/10.1038/nature04055 PMid:16258536

152. Li, Q., et al., Glycerol monolaurate prevents mucosal SIV transmission. Nature, 2009. 458(7241): p. 1034-8. https://doi.org/10.1038/nature07831 PMid:19262509 PMCid:PMC2785041

153. Miller, C.J., et al., Propagation and dissemination of infection after vaginal transmission of simian immunodeficiency virus. J Virol, 2005. 79(14): p. 9217-27. https://doi.org/10.1128/JVI.79.14.9217-9227.2005 PMid:15994816 PMCid:PMC1168785

154. Coffin, J. and R. Swanstrom, HIV pathogenesis: dynamics and genetics of viral populations and infected cells. Cold Spring Harb Perspect Med, 2013. 3(1): p. a012526. https://doi.org/10.1101/cshperspect.a012526 PMid:23284080 PMCid:PMC3530041

155. Walker, B. and A. McMichael, The T-cell response to HIV. Cold Spring Harb Perspect Med, 2012. 2(11). https://doi.org/10.1101/cshperspect.a007054 PMid:23002014 PMCid:PMC3543107

156. Chun, T.W., et al., Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci U S A, 1997. 94(24): p. 13193-7. https://doi.org/10.1073/pnas.94.24.13193 PMid:9371822 PMCid:PMC24285

157. Chun, T.W., et al., Early establishment of a pool of latently infected, resting CD4(+) T cells during primary HIV-1 infection. Proc Natl Acad Sci U S A, 1998. 95(15): p. 8869-73. https://doi.org/10.1073/pnas.95.15.8869 PMid:9671771 PMCid:PMC21169

158. Siliciano, R.F. and W.C. Greene, HIV latency. Cold Spring Harb Perspect Med, 2011. 1(1): p. a007096. https://doi.org/10.1101/cshperspect.a007096 PMid:22229121 PMCid:PMC3234450

159. Bruner, K.M., et al., Defective proviruses rapidly accumulate during acute HIV-1 infection. Nat Med, 2016. 22(9): p. 1043-9. https://doi.org/10.1038/nm.4156 PMid:27500724 PMCid:PMC5014606

160. Hiener, B., et al., Identification of Genetically Intact HIV-1 Proviruses in Specific CD4(+) T Cells from Effectively Treated Participants. Cell Rep, 2017. 21(3): p. 813-822. https://doi.org/10.1016/j.celrep.2017.09.081 PMid:29045846 PMCid:PMC5960642

161. Bruner, K.M., et al., A quantitative approach for measuring the reservoir of latent HIV-1 proviruses. Nature, 2019. 566(7742): p. 120-125. https://doi.org/10.1038/s41586-019-0898-8 PMid:30700913

162. Koenig, R.E., T. Gautier, and J.A. Levy, Unusual intrafamilial transmission of human immunodeficiency virus. Lancet, 1986. 2(8507): p. 627. https://doi.org/10.1016/S0140-6736(86)92448-7

162. Chun, T.W., et al., Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy. J Infect Dis, 2008. 197(5): p. 714-20. https://doi.org/10.1086/527324 PMid:18260759

164. Barton, K., A. Winckelmann, and S. Palmer, HIV-1 Reservoirs During Suppressive Therapy. Trends Microbiol, 2016. 24(5): p. 345-355.https://doi.org/10.1016/j.tim.2016.01.006 PMid:26875617 PMCid:PMC5319871

165. Kandathil, A.J., S. Sugawara, and A. Balagopal, Are T cells the only HIV-1 reservoir? Retrovirology, 2016. 13(1): p. 86. https://doi.org/10.1186/s12977-016-0323-4 PMid:27998285 PMCid:PMC5175311

166. Wong, J.K. and S.A. Yukl, Tissue reservoirs of HIV. Curr Opin HIV AIDS, 2016. 11(4): p. 362-70.https://doi.org/10.1097/COH.0000000000000293 PMid:27259045 PMCid:PMC4928570

167. Vanhamel, J., A. Bruggemans, and Z. Debyser, Establishment of latent HIV-1 reservoirs: what do we really know? J Virus Erad, 2019. 5(1): p. 3-9.

168. Siliciano, J.D., et al., Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med, 2003. 9(6): p. 727-8. https://doi.org/10.1038/nm880 PMid:12754504

169. Chomont, N., et al., HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med, 2009. 15(8): p. 893-900. https://doi.org/10.1038/nm.1972 PMid:19543283 PMCid:PMC2859814

170. Whitney, J.B., et al., Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys. Nature, 2014. 512(7512): p. 74-7. https://doi.org/10.1038/nature13594 PMid:25042999 PMCid:PMC4126858

171. Henrich, T.J., et al., HIV-1 persistence following extremely early initiation of antiretroviral therapy (ART) during acute HIV-1 infection: An observational study. PLoS Med, 2017. 14(11): p. e1002417. https://doi.org/10.1371/journal.pmed.1002417 PMid:29112956 PMCid:PMC5675377

172. Hosmane, N.N., et al., Proliferation of latently infected CD4(+) T cells carrying replication-competent HIV-1: Potential role in latent reservoir dynamics. J Exp Med, 2017. 214(4): p. 959-972. https://doi.org/10.1084/jem.20170193 PMid:28341641 PMCid:PMC5379987

173. Maldarelli, F., et al., HIV latency. Specific HIV integration sites are linked to clonal expansion and persistence of infected cells. Science, 2014. 345(6193): p. 179-83. https://doi.org/10.1126/science.1254194 PMid:24968937 PMCid:PMC4262401

174. Murray, A.J., et al., The Latent Reservoir for HIV-1: How Immunologic Memory and Clonal Expansion Contribute to HIV-1 Persistence. J Immunol, 2016. 197(2): p. 407-17. https://doi.org/10.4049/jimmunol.1600343 PMid:27382129 PMCid:PMC4936486

175. Wagner, T.A., et al., HIV latency. Proliferation of cells with HIV integrated into cancer genes contributes to persistent infection. Science, 2014. 345(6196): p. 570-3. https://doi.org/10.1126/science.1256304 PMid:25011556 PMCid:PMC4230336

176. Wang, Z., et al., Expanded cellular clones carrying replication-competent HIV-1 persist, wax, and wane. Proc Natl Acad Sci U S A, 2018. 115(11): p. E2575-E2584. https://doi.org/10.1073/pnas.1720665115 PMid:29483265 PMCid:PMC5856552

177. Maldarelli, F., The role of HIV integration in viral persistence: no more whistling past the proviral graveyard. J Clin Invest, 2016. 126(2): p. 438-47. https://doi.org/10.1172/JCI80564 PMid:26829624 PMCid:PMC4731194

178. Simonetti, F.R., et al., Clonally expanded CD4+ T cells can produce infectious HIV-1 in vivo. Proc Natl Acad Sci U S A, 2016. 113(7): p. 1883-8. https://doi.org/10.1073/pnas.1522675113 PMid:26858442 PMCid:PMC4763755

179. Anderson, E.M. and F. Maldarelli, The role of integration and clonal expansion in HIV infection: live long and prosper. Retrovirology, 2018. 15(1): p. 71. https://doi.org/10.1186/s12977-018-0448-8 PMid:30352600 PMCid:PMC6199739

180. Wiegand, A., et al., Single-cell analysis of HIV-1 transcriptional activity reveals expression of proviruses in expanded clones during ART. Proc Natl Acad Sci U S A, 2017. 114(18): p. E3659-E3668. https://doi.org/10.1073/pnas.1617961114 PMid:28416661 PMCid:PMC5422779

181. Lorenzi, J.C., et al., Paired quantitative and qualitative assessment of the replication-competent HIV-1 reservoir and comparison with integrated proviral DNA. Proc Natl Acad Sci U S A, 2016. 113(49): p. E7908-E7916.

182. Bui, J.K., et al., Proviruses with identical sequences comprise a large fraction of the replication-competent HIV reservoir. PLoS Pathog, 2017. 13(3): p. e1006283. https://doi.org/10.1371/journal.ppat.1006283 PMid:28328934 PMCid:PMC5378418

183. Agosto, L.M., et al., HIV-1-Infected CD4+ T Cells Facilitate Latent Infection of Resting CD4+ T Cells through Cell-Cell Contact. Cell Rep, 2018. 24(8): p. 2088-2100. https://doi.org/10.1016/j.celrep.2018.07.079 PMid:30134170

184. Sigal, A., et al., Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy. Nature, 2011. 477(7362): p. 95-8. https://doi.org/10.1038/nature10347 PMid:21849975

185. Chun, T.W. and A.S. Fauci, Latent reservoirs of HIV: obstacles to the eradication of virus. Proc Natl Acad Sci U S A, 1999. 96(20): p. 10958-61. https://doi.org/10.1073/pnas.96.20.10958 PMid:10500107 PMCid:PMC34225

186. Borrow, P., et al., Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus. Nat Med, 1997. 3(2): p. 205-11. https://doi.org/10.1038/nm0297-205 PMid:9018240

187. Deng, K., et al., Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations. Nature, 2015. 517(7534): p. 381-5. https://doi.org/10.1038/nature14053 PMid:25561180 PMCid:PMC4406054

188. Goulder, P.J., et al., Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nat Med, 1997. 3(2): p. 212-7.https://doi.org/10.1038/nm0297-212 PMid:9018241

189. Kwong, P.D., et al., HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites. Nature, 2002. 420(6916): p. 678-82. https://doi.org/10.1038/nature01188 PMid:12478295

190. Price, D.A., et al., Positive selection of HIV-1 cytotoxic T lymphocyte escape variants during primary infection. Proc Natl Acad Sci U S A, 1997. 94(5): p. 1890-5. https://doi.org/10.1073/pnas.94.5.1890 PMid:9050875 PMCid:PMC20013

191. Richman, D.D., et al., Rapid evolution of the neutralizing antibody response to HIV type 1 infection. Proc Natl Acad Sci U S A, 2003. 100(7): p. 4144-9. https://doi.org/10.1073/pnas.0630530100 PMid:12644702 PMCid:PMC153062

192. Wei, X., et al., Antibody neutralization and escape by HIV-1. Nature, 2003. 422(6929): p. 307-12. https://doi.org/10.1038/nature01470 PMid:12646921

193. Piatak, M., Jr., et al., High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. Science, 1993. 259(5102): p. 1749-54. https://doi.org/10.1126/science.8096089 PMid:8096089

194. Shan, L., et al., Transcriptional Reprogramming during Effector-to-Memory Transition Renders CD4(+) T Cells Permissive for Latent HIV-1 Infection. Immunity, 2017. 47(4): p. 766-775 e3. https://doi.org/10.1016/j.immuni.2017.09.014 PMid:29045905 PMCid:PMC5948104

195. Delannoy, A., M. Poirier, and B. Bell, Cat and Mouse: HIV Transcription in Latency, Immune Evasion and Cure/Remission Strategies. Viruses, 2019. 11(3).https://doi.org/10.3390/v11030269 PMid:30889861 PMCid:PMC6466452

196. Cary, D.C., K. Fujinaga, and B.M. Peterlin, Molecular mechanisms of HIV latency. J Clin Invest, 2016. 126(2): p. 448-54. https://doi.org/10.1172/JCI80565 PMid:26731470 PMCid:PMC4731164

197. Chavez, L., V. Calvanese, and E. Verdin, HIV Latency Is Established Directly and Early in Both Resting and Activated Primary CD4 T Cells. PLoS Pathog, 2015. 11(6): p. e1004955. https://doi.org/10.1371/journal.ppat.1004955 PMid:26067822 PMCid:PMC4466167

198. Tilton, C.A., et al., A combination HIV reporter virus system for measuring post-entry event efficiency and viral outcome in primary CD4+ T cell subsets. J Virol Methods, 2014. 195: p. 164-9. https://doi.org/10.1016/j.jviromet.2013.08.029 PMid:24025341 PMCid:PMC3982591

199. Hrecka, K., et al., Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein. Nature, 2011. 474(7353): p. 658-61. https://doi.org/10.1038/nature10195 PMid:21720370 PMCid:PMC3179858

200. Laguette, N., et al., SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx. Nature, 2011. 474(7353): p. 654-7. https://doi.org/10.1038/nature10117 PMid:21613998 PMCid:PMC3595993

201. Baldauf, H.M., et al., SAMHD1 restricts HIV-1 infection in resting CD4(+) T cells. Nat Med, 2012. 18(11): p. 1682-7. https://doi.org/10.1038/nm.2964 PMid:22972397 PMCid:PMC3828732

202. Descours, B., et al., SAMHD1 restricts HIV-1 reverse transcription in quiescent CD4(+) T-cells. Retrovirology, 2012. 9: p. 87. https://doi.org/10.1186/1742-4690-9-87 PMid:23092122 PMCid:PMC3494655

203. Kilzer, J.M., et al., Roles of host cell factors in circularization of retroviral dna. Virology, 2003. 314(1): p. 460-7. https://doi.org/10.1016/S0042-6822(03)00455-0

204. Martinez-Picado, J., et al., Episomal HIV-1 DNA and its relationship to other markers of HIV-1 persistence. Retrovirology, 2018. 15(1): p. 15. https://doi.org/10.1186/s12977-018-0398-1 PMid:29378611 PMCid:PMC5789633

205. Sengupta, S. and R.F. Siliciano, Targeting the Latent Reservoir for HIV-1. Immunity, 2018. 48(5): p. 872-895. https://doi.org/10.1016/j.immuni.2018.04.030 PMid:29768175 PMCid:PMC6196732

206. Richetta, C., et al., Two-long terminal repeat (LTR) DNA circles are a substrate for HIV-1 integrase. J Biol Chem, 2019. 294(20): p. 8286-8295. https://doi.org/10.1074/jbc.RA118.006755 PMid:30971426

207. Sengupta, S. and R.F. Siliciano, Targeting the Latent Reservoir for HIV-1. Immunity, 2018. 48(5): p. 872-895. https://doi.org/10.1016/j.immuni.2018.04.030 PMid:29768175 PMCid:PMC6196732

208. Davenport, M.P., et al., Functional cure of HIV: the scale of the challenge. Nat Rev Immunol, 2019. 19(1): p. 45-54. https://doi.org/10.1038/s41577-018-0085-4 PMid:30410126

209. Allers, K., et al., Evidence for the cure of HIV infection by CCR5Delta32/Delta32 stem cell transplantation. Blood, 2011. 117(10): p. 2791-9. https://doi.org/10.1182/blood-2010-09-309591 PMid:21148083

210. Hutter, G., et al., Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med, 2009. 360(7): p. 692-8. https://doi.org/10.1056/NEJMoa0802905 PMid:19213682

211. Verheyen, J., et al., Rapid Rebound of a Preexisting CXCR4-tropic Human Immunodeficiency Virus Variant After Allogeneic Transplantation With CCR5 Delta32 Homozygous Stem Cells. Clin Infect Dis, 2019. 68(4): p. 684-687. https://doi.org/10.1093/cid/ciy565 PMid:30020413

212. Persaud, D., et al., Absence of detectable HIV-1 viremia after treatment cessation in an infant. N Engl J Med, 2013. 369(19): p. 1828-35. https://doi.org/10.1056/NEJMoa1302976 PMid:24152233 PMCid:PMC3954754

213. Luzuriaga, K., et al., Viremic relapse after HIV-1 remission in a perinatally infected child. N Engl J Med, 2015. 372(8): p. 786-8. https://doi.org/10.1056/NEJMc1413931 PMid:25693029 PMCid:PMC4440331

214. Ananworanich, J., et al., HIV DNA Set Point is Rapidly Established in Acute HIV Infection and Dramatically Reduced by Early ART. EBioMedicine, 2016. 11: p. 68-72. https://doi.org/10.1016/j.ebiom.2016.07.024 PMid:27460436 PMCid:PMC5049918

215. Laanani, M., et al., Impact of the Timing of Initiation of Antiretroviral Therapy During Primary HIV-1 Infection on the Decay of Cell-Associated HIV-DNA. Clin Infect Dis, 2015. 60(11): p. 1715-21. https://doi.org/10.1093/cid/civ171 PMid:25737374

216. Richman, D.D., et al., The challenge of finding a cure for HIV infection. Science, 2009. 323(5919): p. 1304-7. https://doi.org/10.1126/science. PMid:19265012

217. Deeks, S.G., HIV: Shock and kill. Nature, 2012. 487(7408): p. 439-40. https://doi.org/10.1038/487439a PMid:22836995

218. Archin, N.M., et al., Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature, 2012. 487(7408): p. 482-5. https://doi.org/10.1038/nature11286 PMid:22837004 PMCid:PMC3704185

219. Archin, N.M. and D.M. Margolis, Emerging strategies to deplete the HIV reservoir. Curr Opin Infect Dis, 2014. 27(1): p. 29-35. https://doi.org/10.1097/QCO.0000000000000026 PMid:24296585 PMCid:PMC4031321

220. Shan, L., et al., Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation. Immunity, 2012. 36(3): p. 491-501. https://doi.org/10.1016/j.immuni.2012.01.014 PMid:22406268 PMCid:PMC3501645

221. Eriksson, S., et al., Comparative analysis of measures of viral reservoirs in HIV-1 eradication studies. PLoS Pathog, 2013. 9(2): p. e1003174. https://doi.org/10.1371/journal.ppat.1003174 PMid:23459007 PMCid:PMC3573107

222. Crooks, A.M., et al., Precise Quantitation of the Latent HIV-1 Reservoir: Implications for Eradication Strategies. J Infect Dis, 2015. 212(9): p. 1361-5. https://doi.org/10.1093/infdis/jiv218 PMid:25877550 PMCid:PMC4601910

223. Cohn, L.B., et al., HIV-1 integration landscape during latent and active infection. Cell, 2015. 160(3): p. 420-32. https://doi.org/10.1016/j.cell.2015.01.020 PMid:25635456 PMCid:PMC4371550

224. Imamichi, H., et al., Defective HIV-1 proviruses produce novel protein-coding RNA species in HIV-infected patients on combination antiretroviral therapy. Proc Natl Acad Sci U S A, 2016. 113(31): p. 8783-8. https://doi.org/10.1073/pnas.1609057113 PMid:27432972 PMCid:PMC4978246

225. Pollack, R.A., et al., Defective HIV-1 Proviruses Are Expressed and Can Be Recognized by Cytotoxic T Lymphocytes, which Shape the Proviral Landscape. Cell Host Microbe, 2017. 21(4): p. 494-506 e4. https://doi.org/10.1016/j.chom.2017.03.008 PMid:28407485 PMCid:PMC5433942

226. Kim, Y., J.L. Anderson, and S.R. Lewin, Getting the "Kill" into "Shock and Kill": Strategies to Eliminate Latent HIV. Cell Host Microbe, 2018. 23(1): p. 14-26. https://doi.org/10.1016/j.chom.2017.12.004 PMid:29324227 PMCid:PMC5990418

227. Spina, C.A., et al., An in-depth comparison of latent HIV-1 reactivation in multiple cell model systems and resting CD4+ T cells from aviremic patients. PLoS Pathog, 2013. 9(12): p. e1003834. https://doi.org/10.1371/journal.ppat.1003834 PMid:24385908 PMCid:PMC3873446

228. Kim, M., et al., A primary CD4(+) T cell model of HIV-1 latency established after activation through the T cell receptor and subsequent return to quiescence. Nat Protoc, 2014. 9(12): p. 2755-70. https://doi.org/10.1038/nprot.2014.188 PMid:25375990 PMCid:PMC4378543

229. Deeks, S.G., et al., Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load. Blood, 2004. 104(4): p. 942-7. https://doi.org/10.1182/blood-2003-09-3333 PMid:15117761

230. Gandhi, R.T. and B.D. Walker, Immunologic control of HIV-1. Annu Rev Med, 2002. 53: p. 149-72. https://doi.org/10.1146/annurev.med.53.082901.104011 PMid:11818468

231. Ogg, G.S., et al., Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. Science, 1998. 279(5359): p. 2103-6. https://doi.org/10.1126/science.279.5359.2103 PMid:9516110

232. Hewitt, E.W. The MHC class I antigen presentation pathway: strategies for viral immune evasion. Immunology. 2003. 110(2): p. 163-169 DOI:10.1046/j.1365-2567.2003.01738.x PMID: 14511229 PMCID: PMC1783040

233. Dustin, M.L. and E.O. Long, Cytotoxic immunological synapses. Immunol Rev, 2010. 235(1): p. 24-34. https://doi.org/10.1111/j.0105-2896.2010.00904.x PMid:20536553 PMCid:PMC2950621

234. Halle, S., O. Halle, and R. Forster, Mechanisms and Dynamics of T Cell-Mediated Cytotoxicity In Vivo. Trends Immunol, 2017. 38(6): p. 432-443. https://doi.org/10.1016/j.it.2017.04.002 PMid:28499492

235. Yang, O.O., et al., Efficient lysis of human immunodeficiency virus type 1-infected cells by cytotoxic T lymphocytes. J Virol, 1996. 70(9): p. 5799-806.

236. Schmitz, J.E., et al., Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science, 1999. 283(5403): p. 857-60. https://doi.org/10.1126/science.283.5403.857 PMid:9933172

237. Allen, T.M., et al., Selective escape from CD8+ T-cell responses represents a major driving force of human immunodeficiency virus type 1 (HIV-1) sequence diversity and reveals constraints on HIV-1 evolution. J Virol, 2005. 79(21): p. 13239-49. https://doi.org/10.1128/JVI.79.21.13239-13249.2005 PMid:16227247 PMCid:PMC1262562

238. Cao, J., et al., Evolution of CD8+ T cell immunity and viral escape following acute HIV-1 infection. J Immunol, 2003. 171(7): p. 3837-46. https://doi.org/10.4049/jimmunol.171.7.3837 PMid:14500685

239. Goulder, P.J., et al., Evolution and transmission of stable CTL escape mutations in HIV infection. Nature, 2001. 412(6844): p. 334-8. https://doi.org/10.1038/35085576 PMid:11460164

240. Cocchi, F., et al., Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science, 1995. 270(5243): p. 1811-5. https://doi.org/10.1126/science.270.5243.1811 PMid:8525373

241. Zanussi, S., et al., CD8+ lymphocyte phenotype and cytokine production in long-term non-progressor and in progressor patients with HIV-1 infection. Clin Exp Immunol, 1996. 105(2): p. 220-4. https://doi.org/10.1046/j.1365-2249.1996.d01-746.x PMid:8706325 PMCid:PMC2200507

242. Migueles, S.A. and M. Connors, Success and failure of the cellular immune response against HIV-1. Nat Immunol, 2015. 16(6): p. 563-70. https://doi.org/10.1038/ni.3161 PMid:25988888

243. Moore, C.B., et al., Evidence of HIV-1 adaptation to HLA-restricted immune responses at a population level. Science, 2002. 296(5572): p. 1439-43. https://doi.org/10.1126/science.1069660 PMid:12029127

244. Martin, E., et al., Early immune adaptation in HIV-1 revealed by population-level approaches. Retrovirology, 2014. 11: p. 64. https://doi.org/10.1186/PREACCEPT-8878001841312932 PMid:25212686 PMCid:PMC4190299

245. Carlson, J.M., et al., HIV-1 adaptation to HLA: a window into virus-host immune interactions. Trends Microbiol, 2015. 23(4): p. 212-24. https://doi.org/10.1016/j.tim.2014.12.008 PMid:25613992

246. Wang, C., M. Singer, and A.C. Anderson, Molecular Dissection of CD8(+) T-Cell Dysfunction. Trends Immunol, 2017. 38(8): p. 567-576. https://doi.org/10.1016/j.it.2017.05.008 PMid:28662970 PMCid:PMC5759349

247. Du, Y., et al., Effects of Mutations on Replicative Fitness and Major Histocompatibility Complex Class I Binding Affinity Are Among the Determinants Underlying Cytotoxic-T-Lymphocyte Escape of HIV-1 Gag Epitopes. MBio, 2017. 8(6). https://doi.org/10.1128/mBio.01050-17 PMid:29184023 PMCid:PMC5705913

248. Kloverpris, H.N., et al., CD8+ TCR Bias and Immunodominance in HIV-1 Infection. J Immunol, 2015. 194(11): p. 5329-45. https://doi.org/10.4049/jimmunol.1400854 PMid:25911754 PMCid:PMC4433859

249. Goepfert, P.A., et al., Transmission of HIV-1 Gag immune escape mutations is associated with reduced viral load in linked recipients. J Exp Med, 2008. 205(5): p. 1009-17. https://doi.org/10.1084/jem.20072457 PMid:18426987 PMCid:PMC2373834

250. Crawford, H., et al., Evolution of HLA-B*5703 HIV-1 escape mutations in HLA-B*5703-positive individuals and their transmission recipients. J Exp Med, 2009. 206(4): p. 909-21. https://doi.org/10.1084/jem.20081984 PMid:19307327 PMCid:PMC2715113

251. Adland, E., et al., Discordant Impact of HLA on Viral Replicative Capacity and Disease Progression in Pediatric and Adult HIV Infection. PLoS Pathog, 2015. 11(6): p. e1004954. https://doi.org/10.1371/journal.ppat.1004954 PMid:26076345 PMCid:PMC4468173

252. Carlson, J.M., et al., HIV transmission. Selection bias at the heterosexual HIV-1 transmission bottleneck. Science, 2014. 345(6193): p. 1254031.

253. Day, C.L., et al., PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature, 2006. 443(7109): p. 350-4. https://doi.org/10.1038/nature05115 PMid:16921384

254. Trautmann, L., et al., Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med, 2006. 12(10): p. 1198-202. https://doi.org/10.1038/nm1482 PMid:16917489

255. Cartwright, E.K., et al., CD8(+) Lymphocytes Are Required for Maintaining Viral Suppression in SIV-Infected Macaques Treated with Short-Term Antiretroviral Therapy. Immunity, 2016. 45(3): p. 656-668. https://doi.org/10.1016/j.immuni.2016.08.018 PMid:27653601 PMCid:PMC5087330

256. Huang, S.H., et al., Latent HIV reservoirs exhibit inherent resistance to elimination by CD8+ T cells. J Clin Invest, 2018. 128(2): p. 876-889. https://doi.org/10.1172/JCI97555 PMid:29355843 PMCid:PMC5785246

257. Sacha, J.B., et al., Gag-specific CD8+ T lymphocytes recognize infected cells before AIDS-virus integration and viral protein expression. J Immunol, 2007. 178(5): p. 2746-54. https://doi.org/10.4049/jimmunol.178.5.2746 PMid:17312117 PMCid:PMC4520734

258. Payne, R.P., et al., Efficacious early antiviral activity of HIV Gag- and Pol-specific HLA-B 2705-restricted CD8+ T cells. J Virol, 2010. 84(20): p. 10543-57. https://doi.org/10.1128/JVI.00793-10 PMid:20686036 PMCid:PMC2950555

259. Kloverpris, H.N., et al., HLA-specific intracellular epitope processing shapes an immunodominance pattern for HLA-B*57 that is distinct from HLA-B*58:01. J Virol, 2013. 87(19): p. 10889-94. https://doi.org/10.1128/JVI.01122-13 PMid:23864640 PMCid:PMC3807415

260. Buckheit, R.W., 3rd, R.F. Siliciano, and J.N. Blankson, Primary CD8+ T cells from elite suppressors effectively eliminate non-productively HIV-1 infected resting and activated CD4+ T cells. Retrovirology, 2013. 10: p. 68. https://doi.org/10.1186/1742-4690-10-68 PMid:23816179 PMCid:PMC3702406

261. Monel, B., et al., HIV Controllers Exhibit Effective CD8(+) T Cell Recognition of HIV-1-Infected Non-activated CD4(+) T Cells. Cell Rep, 2019. 27(1): p. 142-153 e4. https://doi.org/10.1016/j.celrep.2019.03.016 PMid:30943397 PMCid:PMC6449512

262. Saez-Cirion, A., et al., Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS Pathog, 2013. 9(3): p. e1003211. https://doi.org/10.1371/journal.ppat.1003211 PMid:23516360 PMCid:PMC3597518

263. Walker, B.D., Elite control of HIV Infection: implications for vaccines and treatment. Top HIV Med, 2007. 15(4): p. 134-6.

264. Naranbhai, V. and M. Carrington, Host genetic variation and HIV disease: from mapping to mechanism. Immunogenetics, 2017. 69(8-9): p. 489-498. https://doi.org/10.1007/s00251-017-1000-z PMid:28695282 PMCid:PMC5537324

265. Blankson, J.N., Effector mechanisms in HIV-1 infected elite controllers: highly active immune responses? Antiviral Res, 2010. 85(1): p. 295-302. https://doi.org/10.1016/j.antiviral.2009.08.007 PMid:19733595 PMCid:PMC2814919

266. Blankson, J.N., Control of HIV-1 replication in elite suppressors. Discov Med, 2010. 9(46): p. 261-6.

267. Migueles, S.A., et al., Lytic granule loading of CD8+ T cells is required for HIV-infected cell elimination associated with immune control. Immunity, 2008. 29(6): p. 1009-21. https://doi.org/10.1016/j.immuni.2008.10.010 PMid:19062316 PMCid:PMC2622434

268. Ndhlovu, Z.M., et al., High-dimensional immunomonitoring models of HIV-1-specific CD8 T-cell responses accurately identify subjects achieving spontaneous viral control. Blood, 2013. 121(5): p. 801-11. https://doi.org/10.1182/blood-2012-06-436295 PMid:23233659 PMCid:PMC3563365

269. Gonzalo-Gil, E., U. Ikediobi, and R.E. Sutton, Mechanisms of Virologic Control and Clinical Characteristics of HIV+ Elite/Viremic Controllers. Yale J Biol Med, 2017. 90(2): p. 245-259.

270. Buckheit, R.W., 3rd, et al., Host factors dictate control of viral replication in two HIV-1 controller/chronic progressor transmission pairs. Nat Commun, 2012. 3: p. 716. https://doi.org/10.1038/ncomms1697 PMid:22395607 PMCid:PMC3549550

271. Carrington, M. and B.D. Walker, Immunogenetics of spontaneous control of HIV. Annu Rev Med, 2012. 63: p. 131-45. https://doi.org/10.1146/annurev-med-062909-130018 PMid:22248321 PMCid:PMC3725592

272. Goulder, P. and S.G. Deeks, HIV control: Is getting there the same as staying there? PLoS Pathog, 2018. 14(11): p. e1007222. https://doi.org/10.1371/journal.ppat.1007222 PMid:30383857 PMCid:PMC6211749

273. Goulder, P.J. and B.D. Walker, HIV and HLA class I: an evolving relationship. Immunity, 2012. 37(3): p. 426-40. https://doi.org/10.1016/j.immuni.2012.09.005 PMid:22999948 PMCid:PMC3966573

274. Loffredo, J.T., et al., Two MHC class I molecules associated with elite control of immunodeficiency virus replication, Mamu-B*08 and HLA-B*2705, bind peptides with sequence similarity. J Immunol, 2009. 182(12): p. 7763-75. https://doi.org/10.4049/jimmunol.0900111 PMid:19494300 PMCid:PMC2701622

275. Mothe, B.R., et al., Characterization of the peptide-binding specificity of Mamu-B*17 and identification of Mamu-B*17-restricted epitopes derived from simian immunodeficiency virus proteins. J Immunol, 2002. 169(1): p. 210-9. https://doi.org/10.4049/jimmunol.169.1.210 PMid:12077247

276. Loffredo, J.T., et al., Patterns of CD8+ immunodominance may influence the ability of Mamu-B*08-positive macaques to naturally control simian immunodeficiency virus SIVmac239 replication. J Virol, 2008. 82(4): p. 1723-38. https://doi.org/10.1128/JVI.02084-07 PMid:18057253 PMCid:PMC2258706.

277. Loffredo, J.T., et al., CD8+ T cells from SIV elite controller macaques recognize Mamu-B*08-bound epitopes and select for widespread viral variation. PLoS One, 2007. 2(11): p. e1152. https://doi.org/10.1371/journal.pone.0001152 PMid:18000532 PMCid:PMC2062500

278. Loffredo, J.T., et al., Mamu-B*08-positive macaques control simian immunodeficiency virus replication. J Virol, 2007. 81(16): p. 8827-32. https://doi.org/10.1128/JVI.00895-07 PMid:17537848 PMCid:PMC1951344

279. Betts, M.R., et al., HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood, 2006. 107(12): p. 4781-9. https://doi.org/10.1182/blood-2005-12-4818 PMid:16467198 PMCid:PMC1895811

280. Berger, C.T., et al., High-functional-avidity cytotoxic T lymphocyte responses to HLA-B-restricted Gag-derived epitopes associated with relative HIV control. J Virol, 2011. 85(18): p. 9334-45.https://doi.org/10.1128/JVI.00460-11 PMid:21752903 PMCid:PMC3165743

281. Almeida, J.R., et al., Superior control of HIV-1 replication by CD8+ T cells is reflected by their avidity, polyfunctionality, and clonal turnover. J Exp Med, 2007. 204(10): p. 2473-85. https://doi.org/10.1084/jem.20070784 PMid:17893201 PMCid:PMC2118466

282. Saez-Cirion, A., et al., HIV controllers exhibit potent CD8 T cell capacity to suppress HIV infection ex vivo and peculiar cytotoxic T lymphocyte activation phenotype. Proc Natl Acad Sci U S A, 2007. 104(16): p. 6776-81. https://doi.org/10.1073/pnas.0611244104 PMid:17428922 PMCid:PMC1851664

283. Carriere, M., et al., HIV "elite controllers" are characterized by a high frequency of memory CD8+ CD73+ T cells involved in the antigen-specific CD8+ T-cell response. J Infect Dis, 2014. 209(9): p. 1321-30. https://doi.org/10.1093/infdis/jit643 PMid:24357632

284. Zhang, J.Y., et al., PD-1 up-regulation is correlated with HIV-specific memory CD8+ T-cell exhaustion in typical progressors but not in long-term nonprogressors. Blood, 2007. 109(11): p. 4671-8. https://doi.org/10.1182/blood-2006-09-044826 PMid:17272504

285. Mendoza, D., et al., Comprehensive analysis of unique cases with extraordinary control over HIV replication. Blood, 2012. 119(20): p. 4645-55. https://doi.org/10.1182/blood-2011-10-381996 PMid:22490332 PMCid:PMC3367872

286. Elahi, S., et al., Protective HIV-specific CD8+ T cells evade Treg cell suppression. Nat Med, 2011. 17(8): p. 989-95. https://doi.org/10.1038/nm.2422 PMid:21765403 PMCid:PMC3324980

287. Buckheit, R.W., 3rd, et al., Inhibitory potential of subpopulations of CD8+ T cells in HIV-1-infected elite suppressors. J Virol, 2012. 86(24): p. 13679-88. https://doi.org/10.1128/JVI.02439-12 PMid:23055552 PMCid:PMC3503034

288.Borghans, J.A., et al., HLA alleles associated with slow progression to AIDS truly prefer to present HIV-1 p24. PLoS One, 2007. 2(9): p. e920. https://doi.org/10.1371/journal.pone.0000920 PMid:17878955 PMCid:PMC1976389

289. Gorin, A.M., et al., HIV-1 epitopes presented by MHC class I types associated with superior immune containment of viremia have highly constrained fitness landscapes. PLoS Pathog, 2017. 13(8): p. e1006541. https://doi.org/10.1371/journal.ppat.1006541 PMid:28787455 PMCid:PMC5560751

290. Bartha, I., et al., A genome-to-genome analysis of associations between human genetic variation, HIV-1 sequence diversity, and viral control. Elife, 2013. 2: p. e01123. https://doi.org/10.7554/eLife.01123 PMid:24171102 PMCid:PMC3807812

291. Bartha, I., et al., Estimating the Respective Contributions of Human and Viral Genetic Variation to HIV Control. PLoS Comput Biol, 2017. 13(2): p. e1005339. https://doi.org/10.1371/journal.pcbi.1005339 PMid:28182649 PMCid:PMC5300119

292. Chen, H., et al., Differential neutralization of human immunodeficiency virus (HIV) replication in autologous CD4 T cells by HIV-specific cytotoxic T lymphocytes. J Virol, 2009. 83(7): p. 3138-49. https://doi.org/10.1128/JVI.02073-08 PMid:19158248 PMCid:PMC2655558

293. Kiepiela, P., et al., CD8+ T-cell responses to different HIV proteins have discordant associations with viral load. Nat Med, 2007. 13(1): p. 46-53. https://doi.org/10.1038/nm1520 PMid:17173051

294. Kelleher, A.D., et al., Clustered mutations in HIV-1 gag are consistently required for escape from HLA-B27-restricted cytotoxic T lymphocyte responses. J Exp Med, 2001. 193(3): p. 375-86. https://doi.org/10.1084/jem.193.3.375 PMid:11157057 PMCid:PMC2195921

295. Schneidewind, A., et al., Escape from the dominant HLA-B27-restricted cytotoxic T-lymphocyte response in Gag is associated with a dramatic reduction in human immunodeficiency virus type 1 replication. J Virol, 2007. 81(22): p. 12382-93. https://doi.org/10.1128/JVI.01543-07 PMid:17804494 PMCid:PMC2169010

296. Schneidewind, A., et al., Structural and functional constraints limit options for cytotoxic T-lymphocyte escape in the immunodominant HLA-B27-restricted epitope in human immunodeficiency virus type 1 capsid. J Virol, 2008. 82(11): p. 5594-605. https://doi.org/10.1128/JVI.02356-07 PMid:18385228 PMCid:PMC2395179

297. Feeney, M.E., et al., Immune escape precedes breakthrough human immunodeficiency virus type 1 viremia and broadening of the cytotoxic T-lymphocyte response in an HLA-B27-positive long-term-nonprogressing child. J Virol, 2004. 78(16): p. 8927-30. https://doi.org/10.1128/JVI.78.16.8927-8930.2004 PMid:15280502 PMCid:PMC479057

298.Battivelli, E., et al., Gag cytotoxic T lymphocyte escape mutations can increase sensitivity of HIV-1 to human TRIM5alpha, linking intrinsic and acquired immunity. J Virol, 2011. 85(22): p. 11846-54. https://doi.org/10.1128/JVI.05201-11 PMid:21917976 PMCid:PMC3209307

299. Granier, C., et al., Pressure from TRIM5alpha contributes to control of HIV-1 replication by individuals expressing protective HLA-B alleles. J Virol, 2013. 87(18): p. 10368-80. https://doi.org/10.1128/JVI.01313-13 PMid:23864638 PMCid:PMC3753996

300. Merindol, N., et al., HIV-1 capsids from B27/B57+ elite controllers escape Mx2 but are targeted by TRIM5alpha, leading to the induction of an antiviral state. PLoS Pathog, 2018. 14(11): p. e1007398. https://doi.org/10.1371/journal.ppat.1007398 PMid:30419009 PMCid:PMC6258467

301. Joglekar, A.V., et al., T cell receptors for the HIV KK10 epitope from patients with differential immunologic control are functionally indistinguishable. Proc Natl Acad Sci U S A, 2018. 115(8): p. 1877-1882. https://doi.org/10.1073/pnas.1718659115 PMid:29437954 PMCid:PMC5828616

302. Hansen, S.G., et al., Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine. Nature, 2011. 473(7348): p. 523-7.https://doi.org/10.1038/nature10003 PMid:21562493 PMCid:PMC3102768

303. Hansen, S.G., et al., Immune clearance of highly pathogenic SIV infection. Nature, 2013. 502(7469): p. 100-4.
https://doi.org/10.1038/nature12519 PMid:24025770 PMCid:PMC3849456

304. Pernas, B., et al., Plasma mitochondrial DNA levels are inversely associated with HIV-RNA levels and directly with CD4 counts: potential role as a biomarker of HIV replication. J Antimicrob Chemother, 2017. 72(11): p. 3159-3162. https://doi.org/10.1093/jac/dkx272 PMid:28961892

305. Rodriguez-Gallego, E., et al., A baseline metabolomic signature is associated with immunological CD4+ T-cell recovery after 36 months of antiretroviral therapy in HIV-infected patients. AIDS, 2018. 32(5): p. 565-573. https://doi.org/10.1097/QAD.0000000000001730 PMid:29280761 PMCid:PMC5844590

306. Bruel, T. and O. Schwartz, Markers of the HIV-1 reservoir: facts and controversies. Curr Opin HIV AIDS, 2018. 13(5): p. 383-388.https://doi.org/10.1097/COH.0000000000000482 PMid:29846244

307. Chowdhury, F.Z., et al., Metabolic pathway activation distinguishes transcriptional signatures of CD8+ T cells from HIV-1 elite controllers. AIDS, 2018. 32(18): p. 2669-2677. https://doi.org/10.1097/QAD.0000000000002007 PMid:30289807

308. Hocini, H., et al., HIV Controllers Have Low Inflammation Associated with a Strong HIV-Specific Immune Response in Blood. J Virol, 2019. 93(10). https://doi.org/10.1128/JVI.01690-18 PMid:30814287

309. Tarancon-Diez, L., et al., Immunometabolism is a key factor for the persistent spontaneous elite control of HIV-1 infection. EBioMedicine, 2019. 42: p. 86-96. https://doi.org/10.1016/j.ebiom.2019.03.004 PMid:30879922 PMCid:PMC6491381