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Current Opinion in HIV & AIDS:
doi: 10.1097/COH.0b013e328361faf4
THIRTY YEARS OF HIV AND AIDS: Edited by David A. Cooper and Giuseppe Pantaleo

Immune response to HIV

Perreau, Matthieua; Levy, Yvesc; Pantaleo, Giuseppea,b

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aDivision of Immunology and Allergy

bSwiss Vaccine Research Institute, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland

cINSERM U955, Université Paris Est Créteil, Faculté de Médecine, Groupe Henri-Mondor Albert-Chenevier, Immunologie Clinique, Vaccine Research Institute, Creteil, France

Correspondence to Matthieu Perreau, Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois, Rue Bugnon 46, 1011 Lausanne, Switzerland. Tel: +41 2 131 41073; e-mail: matthieu.perreau@chuv.ch

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Abstract

Purpose of review: Major advances have been made in the delineation of HIV-specific immune response and in the mechanisms of virus escape. The kinetics of the immunological and virological events occurring during primary HIV infection indicate that the establishment of the latent HIV reservoir, the major obstacle to HIV eradication likely occurs during the very early stages of primary infection, that is, the ‘eclipse phase’, prior to the development of the HIV-specific immune response which has limited efficacy in the control of the early events of infection. Therefore, the window of opportunity to develop effective interventions either to clear HIV during primary infection or to prevent rebound of HIV in patients successfully treated who stop antiretroviral therapy is very narrow.

Recent findings: Genetic factors most strongly associated with nonprogressive infection are human leukocyte antigen (HLA) class I alleles and particularly HLA-B*5701. CD4 and CD8 T-cell responses with polyfunctional profile are associated with nonprogressive infection. Broader neutralizing antibodies are detected 3–4 years after infection, generated only in 20% of individuals but show no efficacy in the control of HIV replication.

Summary: In the present review, we shall discuss the different components of the HIV-specific immune response elicited by the infection, the kinetics of these responses during primary infection and the changes following transition to the chronic phase of infection, and the functional profile of ‘effective’ versus ‘noneffective’ HIV-specific immune responses.

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INTRODUCTION

Primary HIV infection (PHI) is characterized by a transient symptomatic illness (in 40–90% of cases) associated with high levels of virus replication. In the large majority (>80%) of infected individuals, the transmitted virus results from the infection of a single virus variant as revealed by genome analysis of viral RNA isolated during PHI [1]. Symptoms are not specific to HIV but typical of an acute viral syndrome and may include fever, fatigue, rash, headache, lymphadenopathy, pharyngitis, myalgia, arthralgia, aseptic meningitis, retrorbital pain, weight loss, depression, gastrointestinal distress night sweats, and oral or genital ulcers [2]. The symptomatic phase generally lasts for 2–4 weeks in individuals with ‘normal’ rate of diseases progression, whereas severe and prolonged symptoms are associated with rapid disease progression [3,4]. Once chronic HIV infection is established, the course of HIV disease and progression may be influenced substantially by host (genetic and immunological) and virological factors [5]. At present, there have not been reports of spontaneous, that is, immunologically driven, clearance of HIV following infection. However, a small percentage (1–5% based on case definition) of HIV-infected individuals experience stable disease, that is, lack of decline of CD4 T-cell counts, and control of virus replication below 1000 HIV RNA copies/ml for an extended period of time (at least 7–10 years) in the absence of antiretroviral therapy (ART) [6]. These individuals are called long-term nonprogressors (LTNPs) [7]. Furthermore, an even smaller percentage (<1%) of individuals show control of virus replication below 50 HIV RNA copies/ml regardless of the length of the time of control and are called elite controllers [6]. Rarely, the control of virus replication in LTNPs can be explained by the presence of defective virus [8], and most of them are infected with replication-competent virus, thus indicating that host factors predominantly contribute to virus control and prevention of disease progression.

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KINETICS OF IMMUNE RESPONSE DURING PRIMARY INFECTION

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In order to discuss the kinetics of the different components of the immune response elicited by HIV infection, we will use as a reference the Stages defined by Fiebig on the basis of the kinetics of HIV viral RNA and the appearance of an HIV-specific antibody response [9,10].

Of particular importance is the initial period of infection defined by the so-called ‘eclipse phase’. This phase last for 10 days and defines the period when the virus is not detectable in the plasma [1,11]. Studies performed in rhesus macaques infected with simian immunodeficiency virus (SIV) [12,13] have been instrumental to delineate the events occurring in the ‘eclipse phase’. Virus-infected cells cannot be detected in the mucosa until 1–3 days after infection and the first infected cells are resting memory CD4 T cells expressing CCR5. In addition, submucosal dendritic cells and Langerhans cells uptake the virus from the mucosa through C-type lectins such as DC-SIGN [14,15], which binds HIV gp120 with high affinity [14,15] and internalizes virions and subsequently expresses them on the cell surface after the dendritic cells have matured and migrated to draining lymph nodes where they encounter T cells [14,16–18]. At 1 week postinfection, that is versus the end of the ‘eclipse period’, the virus becomes detectable in the draining lymph nodes where virus production may be amplified as result of spreading of infection among activated T cells that have come in contact with dendritic cells [19,20]. The environment of the lymphoid tissue is ideal for virus replication and spreading due to the large concentration of activated T cells, to the trapping of virions on the extracellular surface of follicular dendritic cells [21–23], and to the abundant production of pro-inflammatory cytokines such as interleukin-1 (IL-1), IL-6, or tumor necrosis factor α (TNF-α) that highly support HIV replication [24]. The immune response to HIV at the end of the ‘eclipse phase’ is stimulated as indicated by the detection of proteins of the acute phase, by the initial detection of inflammatory cytokines resulting from the activation of the innate immune response [24–26], and likely by the stimulation of HIV-specific CD4 T cells. During the ‘eclipse phase’, no effector components of the immune response to HIV capable of containing the initial spreading of infection appear to be operational and after the amplification of the infection in the draining lymph nodes, HIV viral RNA becomes detectable in the plasma (Feibig Stage I) and spreading of the infection to other anatomic compartments such as the gut-associated lymphoid tissues (GALTs) occurs [27]. At the end of the ‘eclipse phase’, HIV begins to spread to the GALT that is predominantly populated of CD4 CCR5+ memory T cells. This results in an exponential expansion of infection, with up to 20% of gut resident CD4 T cells being infected and 80% depleted [27–31]. The large depletion of CD4 T cells occurring in the lymphoid tissues during this stage is indicated by the detection of a number of markers of apoptosis such as TRAIL, microparticles containing CCR5, TNFR2, and soluble FAS ligand as viremia increases [32]. By week 3–4, the levels of viremia peak (generally >107 virus particles per ml of plasma) [9] and it is just at this time that antibody response becomes detectable.

The first wave of antibody response is predominantly composed of anti-gp41 IgG antibodies, which form immune complexes with HIV virions [33]. Immune complexes have been found in the large majority of individuals (90%) during PHI, but only a minority (about 20%) of virions was opsonised by anti-gp41 antibodies and forming immune complexes [33]. The anti-gp41 antibodies bind both infectious and noninfectious virions and lack neutralizing activity [33]. Anti-gp120 antibodies represent a minor component of the antibody response during PHI while become the dominant anti-Env antibody response after the transition to the chronic phase of infection. As viremia peaks and following initial decline, antibodies specific to the other HIV proteins such as Gag are detected by week 3–4 of infection (Feibig Stages III/IV). Taken together, the above observations indicate that the antibody response during PHI has no efficacy in the containment of HIV replication and spreading.

HIV-specific CD8 T-cell response is detected during the increase in viremia levels and generally peaks 1–2 weeks after viremia peak and the peak in CD8 T-cell response coincides with the decline in viremia levels [34,35]. The first wave of CD8 T-cell response is directed predominantly against Env and Nef HIV proteins. The initial CD8 T-cell response appears to have limited or no effect on HIV replication as indicated by the persistence of a homogeneous founder virus without evidence of immune-driven selection of virus escape mutants [36]. It is only at the time of the peak CD8 T-cell response and the decline of viremia that numerous amino acid mutations occur in epitopes of the founder virus recognized by CD8 T cells [36]. No mutations are observed in the escape mutants [36]. The initial CD8 T-cell response is associated with a massive expansion of HIV-specific CD8 T cells [37]. Despite the massive expansion, the initial CD8 T-cell response has likely limited efficacy in the control of virus replication because of the rapid emergence of virus escape mutants and of the rapid disappearance of the responding CD8 T-cell clones due to the lack of recognition of the escape mutants or of exhaustion resulting from high virus/Ag load [36,38].

In the absence of ART, the levels of viremia start to decline around week 4 after infection in order to reach the ‘virologic’ set point generally 12–16 weeks after infection, which marks the transition of the infection to the chronic phase [39]. The contribution of the immune response to the decline of viremia is only partial and predominantly mediated by HIV-specific cytotoxic CD8 T cells that may kill HIV-infected CD4 T cells. However, a major mechanism of the decline may be the lack of cell targets, that is, CD4 T cells, for HIV due to the large depletion of CD4 T cells through direct virus cythopathic effect, killing by CD8 T cells and activation-induced cell death. There is no evidence that the antibody response plays any role in the partial suppression of the decline of viremia and establishment of the ‘virologic’ set point.

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ANTIBODY RESPONSE

Neutralizing antibodies against autologous virus are detected in a large proportion of HIV-infected individuals about 3 months after infection [40] and their appearance is associated with the emergence of mutations in the Env region [41,42]. Neutralizing antibodies with broad neutralizing activity are generated only in a minority (about 20%) of individuals and appear 2–4 years after infection, but there is no evidence of their efficacy in the control of viremia [43–45]. The number of human antibodies with a broad neutralizing activity against a wide range of virus isolates [46–53] remains limited and the majority of neutralizing antibodies has narrow breadth [54].

Numerous phenotypical and functional abnormalities of the B-cell compartment have been described in HIV-infected individuals [55]. These abnormalities include abnormal B-cell activation [56], appearance of transitional immature B cells and exhausted B cells [57,58], and progressive loss of recall responses to vaccination [59].

Passive administration of neutralizing antibodies in nonhuman primates showed protection against SIV challenge, but was dependent upon the titer and the quality of the antibodies [60,61]. In particular, the injection of a cocktail of neutralizing antibodies was able to prevent SIV infection after mucosal virus challenge [62–67]. However, B-cell depletion in monkeys with chronic SIV infection does not influence the levels of plasma viremia [68], thus suggesting that B cells have limited protective role during chronic infection.

Slow progression of HIV disease has been found to be associated with high titers of anti-p24 antibodies [69], with neutralizing antibodies directed against autologous virus [70], or with antibodies against certain gp120 epitopes [71]. Antibodies with broader neutralizing activity have been found more frequently in LTNPs [72–76]. However, it is unclear whether these antibody responses reflect mechanisms of protection or rather the integrity of the immune system in LTNPs.

Finally, mucosal HIV-specific immunoglobulin A (IgA) response has been detected in HIV-exposed uninfected individuals [77]. These IgA may prevent potentially HIV transcytosis through the epithelium [78]. IgA antibodies specific for the gp120-CD4-binding site have also been detected in LTNPs [79].

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THE ROLE OF CD8 T-CELLS IN VIRUS CONTROL

CD8 T cells play a critical role in antiviral immunity [34,35,80–84]. There are a number of observations underscoring the importance of HIV-specific CD8 T cells in the control of virus replication and prevention of disease progression in HIV-infected individuals. These include the rapid loss of control of virus replication after CD8 T-cell depletion in SIV-infected monkeys [80,81,85], the decline of viremia during PHI coinciding with the peak of CD8 T-cell response [35], the presence of CD8 T-cell responses in exposed uninfected individuals [86–89], and the association between protection and HIV-specific CD8 T-cell responses restricted by certain human leukocyte antigen (HLA) class I alleles [90,91].

CD8 T-cell responses from elite controllers compared to progressors have superior capacity to secrete multiple cytokines and chemokines (polyfunctionality), particularly IL-2 [92], to proliferate [93], to inhibit HIV replication in vitro and kill target cells [83,94], to express perforin and degranulate upon HIV-specific stimulation [95–98], and to target Gag epitopes [99,100]. CD8 T-cell responses from elite controllers also inhibited HIV replication without prior activation in vitro, thus suggesting the presence of a pool of CD8 T cells with immediate or rapidly inducible antiviral effector function [92,101–105]. Efficient viral suppression in vitro is predominantly mediated by CD8 T cells specific to Gag rather than Env or Nef [106,107], consistently with the observed protection associated with Gag-specific CD8 T-cell responses detected ex vivo[99].

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THE ROLE OF CD4 T-CELLS IN VIRUS CONTROL

Memory CD4 T cells are the primary targets of HIV [108], and massive depletion of CD4 T cells, particularly of HIV-specific CD4 T cells [109], occurs during PHI. Long-term ART only partially restores the pool of total and HIV-specific memory CD4 T cells [27,28,110,111].

HIV-specific CD4 T cells harbor a skewed functional profile associated with a reduced IL-2 production and proliferation capacity [95,112,113]. This functional impairment was later associated with the expression of coinhibitory molecules [programmed death 1 [114–116], cytotoxic T lymphocyte antigen 4 (CTLA-4) [117]]. Interestingly, a recent study highlighted the functional impairment of follicular helper T cells (Tfh) as responsible for inadequate B-cell help, which may explain some of the functional abnormalities in the B-cell functions observed in HIV infection [118▪▪]. In this regard, it has been recently shown that Tfh serve as the major cell reservoir for HIV, which, in turn, may be responsible for their functional impairment [119▪▪].

Several evidence underscore the importance of CD4 T-cell responses in the control HIV [120]. These include the enrichment in LTNPs and elite controllers of polyfunctional HIV-specific CD4 T cells and preservation of proliferation capacity [84,121–125], the greater production of IL-21 by HIV-specific CD4 T cells in HIV controllers [126,127], the presence of HIV-specific CD4 T cells with higher functional avidity and T-cell receptor-binding affinity in LTNPs [128], the association of some HLA class II alleles with lower viral loads [129,130], and the lower expression of CTLA-4 and other exhaustion markers in HIV-specific CD4 T cells in LTNPs [117].

The superior efficacy of CD8 T cells from elite controllers might also reflect the preservation of the CD4 TCM-cell compartment and of proliferation capacity, which was observed in elite controllers as compared to untreated and treated chronically HIV-infected individuals [121,122,128,131].

In addition, CD4 T cells from elite controllers do not show signs of immune exhaustion such as loss of polyfunctionality and expression of coinhibitory molecules [117,132]. Therefore, these cells are able to secrete IL-2, IL-21, and possibly other cytokines needed to help CD8 T cells in developing and maintaining their effector functions as well as their proliferation capacity and survival [101,121,122,133].

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THE ROLE OF HLA ALLELES IN CONTROL

Whole-genome analysis has demonstrated that the genetic factors most strongly associated with nonprogressive infection are HLA class I alleles and the activating killer cell Ig-like receptor (KIR) allele KIR3DS [90,134–141]. In particular, the HLA-B*5701, HLA-B*5801, and the HLA-B*2705 are associated with slow disease progression, whereas HLA-B*35 with faster disease progression [139,142]. Protective CD8 T-cell responses restricted by HLA-B*5701 and HLA-*B27 recognize the following immunodominant Gag epitopes: TSTLQEQIGW (TW10), KAFSEPVIPMF (KF11), ISPRTLNAW (IW9) restricted by HLA-B*5701, and KRWIILGLNK (KK10) restricted by HLA-B*27 [138,143]. The low viremia is associated with high rate of sequence mutation (reflecting the immunological pressure exerted on epitopes restricted by HLA-B*57), induction of virus variants with reduced replication capacity, and the ability to recognize epitopes with escape mutations [144,145]. The effect of HLA-B on disease outcome seems to be mediated in part by the amino acid position located in the peptide-binding groove, suggesting a difference in the conformation of the peptide presentation [90]. Indeed, intrinsic differences in self-peptide binding among HLA molecules are important during T-cell repertoire development. As fewer self-peptides are able to bind to HLA-B*57 molecules, fewer CD8 T cells restricted by this HLA will undergo negative selection. HLA-B*57-restricted CD8 T cells have higher tolerability for epitope mutations: several mutations in the peptide recognized do not abrogate the recognition capacity by T cells. These observations explain also the association between HLA-B*57 and control of hepatitis C virus (HCV) infection and the association between HLA-B*57 and HLA-B*27 and enhanced risk of autoimmunity [146–148]. Along the same line, KK10-specific CD8 T-cell clones isolated from elite controllers expressing HLA-B*27 were characterized by complementarity determining regions 3 (CDR3) sequences significantly closer to germline sequences, superior ability to control virus replication in vitro, and superior cross-reactivity than KK10-specific CD8 T-cell clones isolated from progressors [105].

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CONCLUSION

HIV-specific T-cell and antibody responses have been extensively characterized in HIV infection. Despite the fact that the magnitude of these responses is orders of magnitude greater as compared to those elicited by other viruses establishing chronic infections, HIV-specific responses fail to effectively control HIV replication and disease progression in the absence of ART in the large majority (>95%) of HIV-infected individuals. Several genetic factors and functional profile of the HIV-specific immune response (particularly in the T-cell response) are associated with protection in LTNPs and elite controllers. These observations together with the recent identification of Tfh cells as the major cell reservoir for HIV infection may guide the future development of therapeutic interventions aimed at the development of strategies that may either stimulate effective T-cell immunity or efficiently target the major HIV cell reservoir, that is, Tfh cells.

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Acknowledgements

None.

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Conflicts of interest

The authors declare no conflict of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 357–359).

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REFERENCES

1. Keele BF, Giorgi EE, Salazar-Gonzalez JF, 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; 105:7552–7557.

2. Kahn JO, Walker BD. Acute human immunodeficiency virus type 1 infection. N Engl J Med 1998; 339:33–39.

3. Dorrucci M, Rezza G, Vlahov D, et al. Clinical characteristics and prognostic value of acute retroviral syndrome among injecting drug users. Italian Seroconversion Study. AIDS 1995; 9:597–604.

4. Henrard DR, Phillips JF, Muenz LR, et al. Natural history of HIV-1 cell-free viremia. JAMA: J Am Med Assoc 1995; 274:554–558.

5. Liu SL, Schacker T, Musey L, et al. Divergent patterns of progression to AIDS after infection from the same source: human immunodeficiency virus type 1 evolution and antiviral responses. J Virol 1997; 71:4284–4295.

6. Walker BD, Korber BT. Immune control of HIV: the obstacles of HLA and viral diversity. Nat Immunol 2001; 2:473–475.

7. Pantaleo G, Menzo S, Vaccarezza M, et al. Studies in subjects with long-term nonprogressive human immunodeficiency virus infection. N Engl J Med 1995; 332:209–216.

8. Kirchhoff F, Greenough TC, Brettler DB, et al. Brief report: absence of intact nef sequences in a long-term survivor with nonprogressive HIV-1 infection. N Engl J Med 1995; 332:228–232.

9. Fiebig EW, Wright DJ, Rawal BD, et al. Dynamics of HIV viremia and antibody seroconversion in plasma donors: implications for diagnosis and staging of primary HIV infection. AIDS 2003; 17:1871–1879.

10. McMichael AJ, Borrow P, Tomaras GD, et al. The immune response during acute HIV-1 infection: clues for vaccine development. Nat Rev Immunol 2010; 10:11–23.

11. Lee HY, Giorgi EE, Keele BF, et al. Modeling sequence evolution in acute HIV-1 infection. J Theor Biol 2009; 261:341–360.

12. Li Q, Duan L, Estes JD, et al. Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells. Nature 2005; 434:1148–1152.

13. Pope M, Haase AT. Transmission, acute HIV-1 infection and the quest for strategies to prevent infection. Nat Med 2003; 9:847–852.

14. Geijtenbeek TB, Kwon DS, Torensma R, et al. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 2000; 100:587–597.

15. Geijtenbeek TB, Torensma R, van Vliet SJ, et al. Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Cell 2000; 100:575–585.

16. Kwon DS, Gregorio G, Bitton N, et al. DC-SIGN-mediated internalization of HIV is required for trans-enhancement of T cell infection. Immunity 2002; 16:135–144.

17. Fong L, Mengozzi M, Abbey NW, et al. Productive infection of plasmacytoid dendritic cells with human immunodeficiency virus type 1 is triggered by CD40 ligation. J Virol 2002; 76:11033–11041.

18. Fonteneau JF, Larsson M, Beignon AS, et al. Human immunodeficiency virus type 1 activates plasmacytoid dendritic cells and concomitantly induces the bystander maturation of myeloid dendritic cells. J Virol 2004; 78:5223–5232.

19. Pope M, Betjes MG, Romani N, et al. Conjugates of dendritic cells and memory T lymphocytes from skin facilitate productive infection with HIV-1. Cell 1994; 78:389–398.

20. Lore K, Smed-Sorensen A, Vasudevan J, et al. Myeloid and plasmacytoid dendritic cells transfer HIV-1 preferentially to antigen-specific CD4+ T cells. J Exp Med 2005; 201:2023–2033.

21. Carter CC, Onafuwa-Nuga A, McNamara LA, et al. HIV-1 infects multipotent progenitor cells causing cell death and establishing latent cellular reservoirs. Nat Med 2010; 16:446–451.

22. Embretson J, Zupancic M, Ribas JL, et al. Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature 1993; 362:359–362.

23. Pantaleo G, Graziosi C, Demarest JF, et al. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature 1993; 362:355–358.

24. Stacey AR, Norris PJ, Qin L, et al. Induction of a striking systemic cytokine cascade prior to peak viremia in acute human immunodeficiency virus type 1 infection, in contrast to more modest and delayed responses in acute hepatitis B and C virus infections. J Virol 2009; 83:3719–3733.

25. Kramer HB, Lavender KJ, Qin L, et al. Elevation of intact and proteolytic fragments of acute phase proteins constitutes the earliest systemic antiviral response in HIV-1 infection. PLoS Pathog 2010; 6:e1000893.

26. Borrow P, Bhardwaj N. Innate immune responses in primary HIV-1 infection. Curr Opin HIV AIDS 2008; 3:36–44.

27. Brenchley JM, Schacker TW, Ruff LE, et al. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med 2004; 200:749–759.

28. Mattapallil JJ, Douek DC, Hill B, et al. Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection. Nature 2005; 434:1093–1097.

29. Veazey RS, Lackner AA. The gastrointestinal tract and the pathogenesis of AIDS. AIDS 1998; 12:S35–S42.

30. Veazey RS, DeMaria M, Chalifoux LV, et al. Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science 1998; 280:427–431.

31. Schindler M, Munch J, Kutsch O, et al. Nef-mediated suppression of T cell activation was lost in a lentiviral lineage that gave rise to HIV-1. Cell 2006; 125:1055–1067.

32. Gasper-Smith N, Crossman DM, Whitesides JF, et al. Induction of plasma (TRAIL), TNFR-2 Fas ligand, and plasma microparticles after human immunodeficiency virus type 1 (HIV-1) transmission: implications for HIV-1 vaccine design. J Virol 2008; 82:7700–7710.

33. Liu P, Overman RG, Yates NL, et al. Dynamic antibody specificities and virion concentrations in circulating immune complexes in acute to chronic HIV-1 infection. J Virol 2011; 85:11196–11207.

34. Borrow P, Lewicki H, Hahn BH, et al. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J Virol 1994; 68:6103–6110.

35. Koup RA, Safrit JT, Cao Y, et al. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol 1994; 68:4650–4655.

36. Goonetilleke N, Liu MK, Salazar-Gonzalez JF, et al. The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection. J Exp Med 2009; 206:1253–1272.

37. Pantaleo G, Demarest JF, Soudeyns H, et al. Major expansion of CD8+ T cells with a predominant V beta usage during the primary immune response to HIV. Nature 1994; 370:463–467.

38. Soudeyns H, Paolucci S, Chappey C, et al. Selective pressure exerted by immunodominant HIV-1-specific cytotoxic T lymphocyte responses during primary infection drives genetic variation restricted to the cognate epitope. Eur J Immunol 1999; 29:3629–3635.

39. Rizzardi GP, Harari A, Capiluppi B, et al. Treatment of primary HIV-1 infection with cyclosporin A coupled with highly active antiretroviral therapy. J Clin Invest 2002; 109:681–688.

40. Alter G, Moody MA. The humoral response to HIV-1: new insights, renewed focus. J Infect Dis 2010; 202 (Suppl 2):S315–S322.

41. Frost SD, Trkola A, Gunthard HF, et al. Antibody responses in primary HIV-1 infection. Curr Opin HIV AIDS 2008; 3:45–51.

42. Richman DD, Wrin T, Little SJ, et al. Rapid evolution of the neutralizing antibody response to HIV type 1 infection. Proc Natl Acad Sci U S A 2003; 100:4144–4149.

43. Gray ES, Moore PL, Choge IA, et al. Neutralizing antibody responses in acute human immunodeficiency virus type 1 subtype C infection. J Virol 2007; 81:6187–6196.

44. Shen X, Parks RJ, Montefiori DC, et al. In vivo gp41 antibodies targeting the 2F5 monoclonal antibody epitope mediate human immunodeficiency virus type 1 neutralization breadth. J Virol 2009; 83:3617–3625.

45. Stamatatos L, Morris L, Burton DR, et al. Neutralizing antibodies generated during natural HIV-1 infection: good news for an HIV-1 vaccine? Nat Med 2009; 15:866–870.

46. Calarese DA, Scanlan CN, Zwick MB, et al. Antibody domain exchange is an immunological solution to carbohydrate cluster recognition. Science 2003; 300:2065–2071.

47. Conley AJ, Kessler JA 2nd, Boots LJ, et al. Neutralization of divergent human immunodeficiency virus type 1 variants and primary isolates by IAM-41-2F5, an antigp41 human monoclonal antibody. Proc Natl Acad Sci U S A 1994; 91:3348–3352.

48. Nelson JD, Brunel FM, Jensen R, et al. An affinity-enhanced neutralizing antibody against the membrane-proximal external region of human immunodeficiency virus type 1 gp41 recognizes an epitope between those of 2F5 and 4E10. J Virol 2007; 81:4033–4043.

49. Roben P, Moore JP, Thali M, et al. Recognition properties of a panel of human recombinant Fab fragments to the CD4 binding site of gp120 that show differing abilities to neutralize human immunodeficiency virus type 1. J Virol 1994; 68:4821–4828.

50. Stiegler G, Kunert R, Purtscher M, et al. A potent cross-clade neutralizing human monoclonal antibody against a novel epitope on gp41 of human immunodeficiency virus type 1. AIDS Res Hum Retroviruses 2001; 17:1757–1765.

51. Trkola A, Pomales AB, Yuan H, et al. Cross-clade neutralization of primary isolates of human immunodeficiency virus type 1 by human monoclonal antibodies and tetrameric CD4-IgG. J Virol 1995; 69:6609–6617.

52. Walker LM, Phogat SK, Chan-Hui PY, et al. Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science 2009; 326:285–289.

53. Zwick MB, Labrijn AF, Wang M, et al. Broadly neutralizing antibodies targeted to the membrane-proximal external region of human immunodeficiency virus type 1 glycoprotein gp41. J Virol 2001; 75:10892–10905.

54. Moore JP, Trkola A, Korber B, et al. A human monoclonal antibody to a complex epitope in the V3 region of gp120 of human immunodeficiency virus type 1 has broad reactivity within and outside clade B. J Virol 1995; 69:122–130.

55. Moir S, Fauci AS. B cells in HIV infection and disease. Nat Rev Immunol 2009; 9:235–245.

56. Lane HC, Masur H, Edgar LC, et al. Abnormalities of B-cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome. N Engl J Med 1983; 309:453–458.

57. Moir S, Fauci AS. Pathogenic mechanisms of B-lymphocyte dysfunction in HIV disease. J Allergy Clin Immunol 2008; 122:12–19.quiz 20 11.

58. Moir S, Ho J, Malaspina A, et al. Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compartment in HIV-infected viremic individuals. J Exp Med 2008; 205:1797–1805.

59. De Milito A. B lymphocyte dysfunctions in HIV infection. Curr HIV Res 2004; 2:11–21.

60. Mascola JR, Stiegler G, VanCott TC, et al. Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies. Nat Med 2000; 6:207–210.

61. Baba TW, Liska V, Hofmann-Lehmann R, et al. Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian-human immunodeficiency virus infection. Nat Med 2000; 6:200–206.

62. Ferrantelli F, Rasmussen RA, Buckley KA, et al. Complete protection of neonatal rhesus macaques against oral exposure to pathogenic simian-human immunodeficiency virus by human anti-HIV monoclonal antibodies. J Infect Dis 2004; 189:2167–2173.

63. Ferrantelli F, Kitabwalla M, Rasmussen RA, et al. Potent cross-group neutralization of primary human immunodeficiency virus isolates with monoclonal antibodies: implications for acquired immunodeficiency syndrome vaccine. J Infect Dis 2004; 189:71–74.

64. Xiao P, Patterson LJ, Kuate S, et al. Replicating adenovirus-simian immunodeficiency virus (SIV) recombinant priming and envelope protein boosting elicits localized, mucosal IgA immunity in rhesus macaques correlated with delayed acquisition following a repeated low-dose rectal SIV(mac251) challenge. J Virol 2012; 86:4644–4657.

65. Hessell AJ, Rakasz EG, Tehrani DM, et al. Broadly neutralizing monoclonal antibodies 2F5 and 4E10 directed against the human immunodeficiency virus type 1 gp41 membrane-proximal external region protect against mucosal challenge by simian-human immunodeficiency virus SHIVBa-L. J Virol 2010; 84:1302–1313.

66. Hessell AJ, Poignard P, Hunter M, et al. Effective, low-titer antibody protection against low-dose repeated mucosal SHIV challenge in macaques. Nat Med 2009; 15:951–954.

67. Hessell AJ, Rakasz EG, Poignard P, et al. Broadly neutralizing human anti-HIV antibody 2G12 is effective in protection against mucosal SHIV challenge even at low serum neutralizing titers. PLoS Pathog 2009; 5:e1000433.

68. Schmitz JE, Kuroda MJ, Santra S, et al. Effect of humoral immune responses on controlling viremia during primary infection of rhesus monkeys with simian immunodeficiency virus. J Virol 2003; 77:2165–2173.

69. Hogervorst E, Jurriaans S, de Wolf F, et al. Predictors for non and slow progression in human immunodeficiency virus (HIV) type 1 infection: low viral RNA copy numbers in serum and maintenance of high HIV-1 p24-specific but not V3-specific antibody levels. J Infect Dis 1995; 171:811–821.

70. Montefiori DC, Pantaleo G, Fink LM, et al. Neutralizing and infection-enhancing antibody responses to human immunodeficiency virus type 1 in long-term nonprogressors. J Infect Dis 1996; 173:60–67.

71. Wong MT, Warren RQ, Anderson SA, et al. Longitudinal analysis of the humoral immune response to human immunodeficiency virus type 1 (HIV-1) gp160 epitopes in rapidly progressing and nonprogressing HIV-1-infected subjects. J Infect Dis 1993; 168:1523–1527.

72. Sajadi MM, Guan Y, DeVico AL, et al. Correlation between circulating HIV-1 RNA and broad HIV-1 neutralizing antibody activity. J Acquir Immune Defic Syndr 2011; 57:9–15.

73. Banerjee K, Klasse PJ, Sanders RW, et al. IgG subclass profiles in infected HIV type 1 controllers and chronic progressors and in uninfected recipients of Env vaccines. AIDS Res Hum Retroviruses 2010; 26:445–458.

74. Bello G, Velasco-de-Castro CA, Bongertz V, et al. Immune activation and antibody responses in nonprogressing elite controller individuals infected with HIV-1. J Med Virol 2009; 81:1681–1690.

75. Pereyra F, Palmer S, Miura T, et al. Persistent low-level viremia in HIV-1 elite controllers and relationship to immunologic parameters. J Infect Dis 2009; 200:984–990.

76. Lambotte O, Ferrari G, Moog C, et al. Heterogeneous neutralizing antibody and antibody-dependent cell cytotoxicity responses in HIV-1 elite controllers. AIDS 2009; 23:897–906.

77. Bunders M, Pembrey L, Kuijpers T, et al. Evidence of impact of maternal HIV infection on immunoglobulin levels in HIV-exposed uninfected children. AIDS Res Hum Retroviruses 2010; 26:967–975.

78. Shen R, Drelichman ER, Bimczok D, et al. GP41-specific antibody blocks cell-free HIV type 1 transcytosis through human rectal mucosa and model colonic epithelium. J Immunol 2010; 184:3648–3655.

79. Planque S, Salas M, Mitsuda Y, et al. Neutralization of genetically diverse HIV-1 strains by IgA antibodies to the gp120-CD4-binding site from long-term survivors of HIV infection. AIDS 2010; 24:875–884.

80. Jin X, Bauer DE, Tuttleton SE, et al. Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virus-infected macaques. J Exp Med 1999; 189:991–998.

81. Schmitz JE, Kuroda MJ, Santra S, et al. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 1999; 283:857–860.

82. Moore CB, John M, James IR, et al. Evidence of HIV-1 adaptation to HLA-restricted immune responses at a population level. Science 2002; 296:1439–1443.

83. Hersperger AR, Pereyra F, Nason M, et al. Perforin expression directly ex vivo by HIV-specific CD8 T-cells is a correlate of HIV elite control. PLoS Pathogens 2010; 6:e1000917.

84. Pereyra F, Addo MM, Kaufmann DE, et al. Genetic and immunologic heterogeneity among persons who control HIV infection in the absence of therapy. J Infect Dis 2008; 197:563–571.

85. O’Connor DH, Allen TM, Vogel TU, et al. Acute phase cytotoxic T lymphocyte escape is a hallmark of simian immunodeficiency virus infection. Nat Med 2002; 8:493–499.

86. Perez CL, Hasselrot K, Bratt G, et al. Induction of systemic HIV-1-specific cellular immune responses by oral exposure in the uninfected partner of discordant couples. AIDS 2010; 24:969–974.

87. Hasselrot K. Genital and oral mucosal immune response against HIV-1 in exposed uninfected individuals. Crit Rev Immunol 2009; 29:369–377.

88. Hasselrot K, Bratt G, Hirbod T, et al. Orally exposed uninfected individuals have systemic anti-HIV responses associating with partners’ viral load. AIDS 2010; 24:35–43.

89. Erickson AL, Willberg CB, McMahan V, et al. Potentially exposed but uninfected individuals produce cytotoxic and polyfunctional human immunodeficiency virus type 1-specific CD8(+) T-cell responses which can be defined to the epitope level. Clin Vaccine Immunol 2008; 15:1745–1748.

90. Pereyra F, Jia X, McLaren PJ, et al. The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. Science 2010; 330:1551–1557.

91. Fellay J, Shianna KV, Ge D, et al. A whole-genome association study of major determinants for host control of HIV-1. Science 2007; 317:944–947.

92. Betts MR, Nason MC, West SM, et al. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 2006; 107:4781–4789.

93. Ndhlovu ZM, Chibnik LB, Proudfoot J, et al. High-dimensional immunomonitoring models of HIV-1-specific CD8 T-cell responses accurately identify subjects achieving spontaneous viral control. Blood 2013; 121:801–811.

94. Migueles SA, Laborico AC, Shupert WL, et al. HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nat Immunol 2002; 3:1061–1068.

95. Harari A, Petitpierre S, Vallelian F, et al. Skewed representation of functionally distinct populations of virus-specific CD4 T cells in HIV-1-infected subjects with progressive disease: changes after antiretroviral therapy. Blood 2004; 103:966–972.

96. Harari A, Dutoit V, Cellerai C, et al. Functional signatures of protective antiviral T-cell immunity in human virus infections. Immunol Rev 2006; 211:236–254.

97. Harari A, Cellerai C, Pantaleo G. Role of HIV-1-specific CD4 T cells. Curr Opin HIV AIDS 2006; 1:22–27.

98. Wherry EJ, Blattman JN, Murali-Krishna K, et al. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol 2003; 77:4911–4927.

99. Kiepiela P, Ngumbela K, Thobakgale C, et al. CD8+ T-cell responses to different HIV proteins have discordant associations with viral load. Nat Med 2007; 13:46–53.

100. Zuniga R, Lucchetti A, Galvan P, et al. Relative dominance of Gag p24-specific cytotoxic T lymphocytes is associated with human immunodeficiency virus control. J Virol 2006; 80:3122–3125.

101. Saez-Cirion A, Lacabaratz C, Lambotte O, 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; 104:6776–6781.

102. Ferre AL, Hunt PW, Critchfield JW, et al. Mucosal immune responses to HIV-1 in elite controllers: a potential correlate of immune control. Blood 2009; 113:3978–3989.

103. Migueles SA, Weeks KA, Nou E, et al. Defective human immunodeficiency virus-specific CD8+ T-cell polyfunctionality, proliferation, and cytotoxicity are not restored by antiretroviral therapy. J Virol 2009; 83:11876–11889.

104. Makedonas G, Hutnick N, Haney D, et al. Perforin and IL-2 upregulation define qualitative differences among highly functional virus-specific human CD8 T cells. PLoS Pathogens 2010; 6:e1000798.

105. Chen H, Ndhlovu ZM, Liu D, et al. TCR clonotypes modulate the protective effect of HLA class I molecules in HIV-1 infection. Nat Immunol 2012; 13:691–700.

106. Saez-Cirion A, Sinet M, Shin SY, et al. Heterogeneity in HIV suppression by CD8 T cells from HIV controllers: association with Gag-specific CD8 T cell responses. J Immunol 2009; 182:7828–7837.

107. Julg B, Williams KL, Reddy S, et al. Enhanced anti-HIV functional activity associated with Gag-specific CD8 T-cell responses. J Virol 2010; 84:5540–5549.

108. Schnittman SM, Lane HC, Greenhouse J, et al. Preferential infection of CD4+ memory T cells by human immunodeficiency virus type 1: evidence for a role in the selective T-cell functional defects observed in infected individuals. Proc Natl Acad Sci U S A 1990; 87:6058–6062.

109. Douek DC, Brenchley JM, Betts MR, et al. HIV preferentially infects HIV-specific CD4+ T cells. Nature 2002; 417:95–98.

110. Guadalupe M, Reay E, Sankaran S, et al. Severe CD4+ T-cell depletion in gut lymphoid tissue during primary human immunodeficiency virus type 1 infection and substantial delay in restoration following highly active antiretroviral therapy. J Virol 2003; 77:11708–11717.

111. Rosenberg ES, Billingsley JM, Caliendo AM, et al. Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 1997; 278:1447–1450.

112. Harari A, Rizzardi GP, Ellefsen K, et al. Analysis of HIV-1- and CMV-specific memory CD4 T-cell responses during primary and chronic infection. Blood 2002; 100:1381–1387.

113. Harari A, Vallelian F, Meylan PR, et al. Functional heterogeneity of memory CD4 T cell responses in different conditions of antigen exposure and persistence. J Immunol 2005; 174:1037–1045.

114. Day CL, Kaufmann DE, Kiepiela P, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 2006; 443:350–354.

115. D'Souza M, Fontenot AP, Mack DG, et al. Programmed death 1 expression on HIV-specific CD4+ T cells is driven by viral replication and associated with T cell dysfunction. J Immunol 2007; 179:1979–1987.

116. Porichis F, Kwon DS, Zupkosky J, et al. Responsiveness of HIV-specific CD4 T cells to PD-1 blockade. Blood 2011; 118:965–974.

117. Kaufmann DE, Kavanagh DG, Pereyra F, et al. Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction. Nat Immunol 2007; 8:1246–1254.

118▪▪. Cubas RA, Mudd JC, Savoye AL, et al. Inadequate T follicular cell help impairs B cell immunity during HIV infection. Nat Med 2013; 19:494–499.

This study demonstrates that the function of T follicular helper cells is abnormal in HIV-infected individuals with chronic HIV infection. These results may help to explain why B-cell and antibody responses are impaired in HIV infection.

119▪▪. Perreau M, Savoye AL, De Crignis E, et al. Follicular helper T cells serve as the major CD4 T cell compartment for HIV-1 infection, replication, and production. J Exp Med 2013; 210:143–156.

In this study, the distribution of HIV-specific and HIV-infected CD4 T cells within different populations of memory CD4 T cells isolated from lymph nodes of viremic HIV-infected individuals was examined. The study shows that the Tfh cell population is enriched in HIV-specific CD4 T cells, and is significantly increased in viremic HIV-infected individuals. The Tfh cell population contained the highest percentage of CD4 T cells harboring HIV DNA and was the most efficient in supporting productive infection in vitro. Furthermore, only the percentage of Tfh cells correlated with plasma viremia levels.

120. Theze J, Chakrabarti LA, Vingert B, et al. HIV controllers: a multifactorial phenotype of spontaneous viral suppression. Clin Immunol 2011; 141:15–30.

121. Potter SJ, Lacabaratz C, Lambotte O, et al. Preserved central memory and activated effector memory CD4+ T-cell subsets in human immunodeficiency virus controllers: an ANRS EP36 study. J Virol 2007; 81:13904–13915.

122. Younes SA, Yassine-Diab B, Dumont AR, et al. HIV-1 viremia prevents the establishment of interleukin 2-producing HIV-specific memory CD4+ T cells endowed with proliferative capacity. J Exp Med 2003; 198:1909–1922.

123. Betts MR, Ambrozak DR, Douek DC, et al. Analysis of total human immunodeficiency virus (HIV)-specific CD4(+) and CD8(+) T-cell responses: relationship to viral load in untreated HIV infection. J Virol 2001; 75:11983–11991.

124. Harari A, Cellerai C, Enders FB, et al. Skewed association of polyfunctional antigen-specific CD8 T cell populations with HLA-B genotype. Proc Natl Acad Sci U S A 2007; 104:16233–16238.

125. Ferre AL, Hunt PW, McConnell DH, et al. HIV controllers with HLA-DRB1*13 and HLA-DQB1*06 alleles have strong, polyfunctional mucosal CD4+ T-cell responses. J Virol 2010; 84:11020–11029.

126. Yue FY, Lo C, Sakhdari A, et al. HIV-specific IL-21 producing CD4+ T cells are induced in acute and chronic progressive HIV infection and are associated with relative viral control. J Immunol 2010; 185:498–506.

127. Chevalier MF, Julg B, Pyo A, et al. HIV-1-specific interleukin-21+ CD4+ T cell responses contribute to durable viral control through the modulation of HIV-specific CD8+ T cell function. J Virol 2011; 85:733–741.

128. Vingert B, Perez-Patrigeon S, Jeannin P, et al. HIV controller CD4+ T cells respond to minimal amounts of Gag antigen due to high TCR avidity. PLoS Pathog 2010; 6:e1000780.

129. Malhotra U, Holte S, Dutta S, et al. Role for HLA class II molecules in HIV-1 suppression and cellular immunity following antiretroviral treatment. J Clin Invest 2001; 107:505–517.

130. Julg B, Pereyra F, Buzon MJ, et al. Infrequent recovery of HIV from but robust exogenous infection of activated CD4(+) T cells in HIV elite controllers. Clin Infect Dis 2010; 51:233–238.

131. Emu B, Sinclair E, Favre D, et al. Phenotypic, functional, and kinetic parameters associated with apparent T-cell control of human immunodeficiency virus replication in individuals with and without antiretroviral treatment. J Virol 2005; 79:14169–14178.

132. Deeks SG, Walker BD. Human immunodeficiency virus controllers: mechanisms of durable virus control in the absence of antiretroviral therapy. Immunity 2007; 27:406–416.

133. van Grevenynghe J, Procopio FA, He Z, et al. Transcription factor FOXO3a controls the persistence of memory CD4(+) T cells during HIV infection. Nat Med 2008; 14:266–274.

134. Kiepiela P, Leslie AJ, Honeyborne I, et al. Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA. Nature 2004; 432:769–775.

135. Chopera DR, Mlotshwa M, Woodman Z, et al. Virological and immunological factors associated with HIV-1 differential disease progression in HLA-B*58:01-positive individuals. J Virol 2011; 85:7070–7080.

136. Peretz Y, Marra O, Thomas R, et al. Relative contribution of HIV-specific functional lymphocyte subsets restricted by protective and non-protective HLA alleles. Viral Immunol 2011; 24:189–198.

137. Payne RP, Kloverpris H, Sacha JB, et al. Efficacious early antiviral activity of HIV Gag- and Pol-specific HLA-B 2705-restricted CD8+ T cells. J Virol 2010; 84:10543–10557.

138. Migueles SA, Sabbaghian MS, Shupert WL, et al. HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors. Proc Nal Acad Sci U S A 2000; 97:2709–2714.

139. Carrington M, O’Brien SJ. The influence of HLA genotype on AIDS. Annu Rev Med 2003; 54:535–551.

140. Martin MP, Gao X, Lee JH, et al. Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS. Nat Genet 2002; 31:429–434.

141. Bashirova AA, Thomas R, Carrington M. HLA/KIR restraint of HIV: surviving the fittest. Annu Rev Immunol 2011; 29:295–317.

142. Carrington M, Walker BD. Immunogenetics of spontaneous control of HIV. Ann Rev Med 2012; 63:131–145.

143. Goulder PJ, Bunce M, Krausa P, et al. Novel, cross-restricted, conserved, and immunodominant cytotoxic T lymphocyte epitopes in slow progressors in HIV type 1 infection. AIDS Res Hum Retroviruses 1996; 12:1691–1698.

144. Bailey JR, Williams TM, Siliciano RF, et al. Maintenance of viral suppression in HIV-1-infected HLA-B*57+ elite suppressors despite CTL escape mutations. J Exp Med 2006; 203:1357–1369.

145. Miura T, Brumme CJ, Brockman MA, et al. HLA-associated viral mutations are common in human immunodeficiency virus type 1 elite controllers. J Virol 2009; 83:3407–3412.

146. Thio CL, Gao X, Goedert JJ, et al. HLA-Cw*04 and hepatitis C virus persistence. J Virol 2002; 76:4792–4797.

147. Chessman D, Kostenko L, Lethborg T, et al. Human leukocyte antigen class I-restricted activation of CD8+ T cells provides the immunogenetic basis of a systemic drug hypersensitivity. Immunity 2008; 28:822–832.

148. Bowness P. HLA B27 in health and disease: a double-edged sword? Rheumatology 2002; 41:857–868.

Keywords:

antibodies; HIV; immune response; T cells

© 2013 Lippincott Williams & Wilkins, Inc.

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