Pilcher, C. D. et al. Detection of acute infections during HIV testing in North Carolina. N. Engl. J. Med. 352, 1873–1883 (2005).
Powers, K. A. et al. Improved detection of acute HIV-1 infection in sub-Saharan Africa: development of a risk score algorithm. AIDS 21, 2237–2242 (2007).
Hu, Q. et al. Blockade of attachment and fusion receptors inhibits HIV-1 infection of human cervical tissue. J. Exp. Med. 199, 1065–1075 (2004).
Veazey, R. S. et al. Protection of macaques from vaginal SHIV challenge by vaginally delivered inhibitors of virus-cell fusion. Nature 438, 99–102 (2005).
Margolis, L. & Shattock, R. Selective transmission of CCR5-utilizing HIV-1: the 'gatekeeper' problem resolved? Nature Rev. Microbiol. 4, 312–317 (2006).
Li, Q. et al. Visualizing antigen-specific and infected cells in situ predicts outcomes in early viral infection. Science 323, 1726–1729 (2009).
Miller, C. J. et al. Propagation and dissemination of infection after vaginal transmission of simian immunodeficiency virus. J. Virol. 79, 9217–9227 (2005).
Sodora, D. L., Gettie, A., Miller, C. J. & Marx, P. A. Vaginal transmission of SIV: assessing infectivity and hormonal influences in macaques inoculated with cell-free and cell-associated viral stocks. AIDS Res. Hum. Retroviruses 14, S119–S123 (1998).
Lai, S. K. et al. Human immunodeficiency virus type 1 is trapped by acidic but not by neutralized human cervicovaginal mucus. J. Virol. 83, 11196–11200 (2009).
Galvin, S. R. & Cohen, M. S. The role of sexually transmitted diseases in HIV transmission. Nature Rev. Microbiol. 2, 33–42 (2004).
Haaland, R. E. et al. Inflammatory genital infections mitigate a severe genetic bottleneck in heterosexual transmission of subtype A and C HIV-1. PLoS Pathog. 5, e1000274 (2009).
Keele, B. F. et al. Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc. Natl Acad. Sci. USA 105, 7552–7557 (2008).
This study used single-genome amplification of viral RNA obtained from patients with acute HIV-1 infection to show that ∼80% of infections arise from a single transmitted or founder virus.
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. 83, 3556–3567 (2009).
Salazar-Gonzalez, J. F. et al. Genetic identity, biological phenotype, and evolutionary pathways of transmitted/founder viruses in acute and early HIV-1 infection. J. Exp. Med. 206, 1273–1289 (2009).
Keele, B. F. et al. Low-dose rectal inoculation of rhesus macaques by SIVsmE660 or SIVmac251 recapitulates human mucosal infection by HIV-1. J. Exp. Med. 206, 1117–1134 (2009).
Li, Q. et al. Glycerol monolaurate prevents mucosal SIV transmission. Nature 458, 1034–1038 (2009).
Bishop, K. N., Holmes, R. K., Sheehy, A. M. & Malim, M. H. APOBEC-mediated editing of viral RNA. Science 305, 645 (2004).
Geijtenbeek, T. B. et al. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 100, 587–597 (2000).
Moir, S. et al. B cells of HIV-1-infected patients bind virions through CD21–complement interactions and transmit infectious virus to activated T cells. J. Exp. Med. 192, 637–646 (2000).
Brenchley, J. M. et al. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J. Exp. Med. 200, 749–759 (2004).
In this study a combination of flow cytometry, endoscopy and histological techniques was used to show that the gastrointestinal tract is the site of the most profound depletion of CCR5+CD4+ T cells at all stages of HIV-1 disease.
Brenchley, J. M. et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nature Med. 12, 1365–1371 (2006).
Brenchley, J. M. et al. Differential Th17 CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections. Blood 112, 2826–2835 (2008).
Gasper-Smith, N. 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. 82, 7700–7710 (2008).
Veazey, R. S. et al. Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science 280, 427–431 (1998).
The first demonstration that activated CD4+ T cells are depleted in the intestine within days of intravenous SIV infection of macaques, showing that the gastrointestinal tract is the major site of SIV replication.
Mattapallil, J. J. et al. Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection. Nature 434, 1093–1097 (2005).
Levesque, M. C. et al. Polyclonal B cell differentiation and loss of gastrointestinal tract germinal centers in the earliest stages of HIV-1 infection. PLoS Med. 6, e1000107 (2009).
This study used flow cytometry, histology and quantitative imaging techniques to show polyclonal B cell activation and destruction of germinal centres in acute HIV-1 infection.
Ho, D. D. et al. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373, 123–126 (1995).
Schacker, T. W., Hughes, J. P., Shea, T., Coombs, R. W. & Corey, L. Biological and virologic characteristics of primary HIV infection. Ann. Intern. Med. 128, 613–620 (1998).
Rodriguez, B. et al. Predictive value of plasma HIV RNA level on rate of CD4 T-cell decline in untreated HIV infection. JAMA 296, 1498–1506 (2006).
Borrow, P., Lewicki, H., Hahn, B. H., Shaw, G. M. & Oldstone, M. B. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J. Virol. 68, 6103–6110 (1994).
Koup, R. A. et al. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J. Virol. 68, 4650–4655 (1994).
Price, D. A. et al. Positive selection of HIV-1 cytotoxic T lymphocyte escape variants during primary infection. Proc. Natl Acad. Sci. USA 94, 1890–1895 (1997).
Wilson, J. D. et al. Direct visualization of HIV-1-specific cytotoxic T lymphocytes during primary infection. AIDS 14, 225–233 (2000).
Markowitz, M. et al. A novel antiviral intervention results in more accurate assessment of human immunodeficiency virus type 1 replication dynamics and T-cell decay in vivo. J. Virol. 77, 5037–5038 (2003).
Sedaghat, A. R., Siliciano, J. D., Brennan, T. P., Wilke, C. O. & Siliciano, R. F. Limits on replenishment of the resting CD4+ T cell reservoir for HIV in patients on HAART. PLoS Pathog. 3, e122 (2007).
Brennan, T. P. et al. Analysis of human immunodeficiency virus type 1 viremia and provirus in resting CD4+ T cells reveals a novel source of residual viremia in patients on antiretroviral therapy. J. Virol. 83, 8470–8481 (2009).
Dinoso, J. B. et al. Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc. Natl Acad. Sci. USA 106, 9403–9408 (2009).
The stable reservoirs of latent HIV-1 infection were first identified in this study.
Finkel, T. H. et al. Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes. Nature Med. 1, 129–134 (1995).
Silvestri, G. et al. Nonpathogenic SIV infection of sooty mangabeys is characterized by limited bystander immunopathology despite chronic high-level viremia. Immunity 18, 441–452 (2003).
This study shows that SIV infected sooty mangabeys have high viral load but low immune activation with no loss of blood CD4+ T cells, suggesting chronic immune activation might be responsible for many of the problems in HIV-1 infection.
Liu, Z. et al. Elevated CD38 antigen expression on CD8+ T cells is a stronger marker for the risk of chronic HIV disease progression to AIDS and death in the Multicenter AIDS Cohort Study than CD4+ cell count, soluble immune activation markers, or combinations of HLA-DR and CD38 expression. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 16, 83–92 (1997).
Giorgi, J. V. et al. Predictive value of immunologic and virologic markers after long or short duration of HIV-1 infection. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 29, 346–355 (2002).
Deeks, S. G. et al. Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load. Blood 104, 942–947 (2004).
This paper shows that the level of immune activation is a better predictor of CD4+ T cell decline than viral load.
Li, Q. et al. Microarray analysis of lymphatic tissue reveals stage-specific, gene expression signatures in HIV-1 infection. J. Immunol. 183, 1975–1982 (2009).
Sodora, D. L. & Silvestri, G. Immune activation and AIDS pathogenesis. AIDS 22, 439–446 (2008).
Gao, F. et al. Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes. Nature 397, 436–441 (1999).
Korber, B. et al. Timing the ancestor of the HIV-1 pandemic strains. Science 288, 1789–1796 (2000).
Keele, B. F. et al. Chimpanzee reservoirs of pandemic and nonpandemic HIV-1. Science 313, 523–526 (2006).
Liu, R. et al. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 86, 367–377 (1996).
Carrington, M. & O'Brien, S. J. The influence of HLA genotype on AIDS. Annu. Rev. Med. 54, 535–551 (2003).
A seminal review that describes the association between HLA-A, HLA-B and HLA-C alleles and the rate of disease progression.
Fellay, J. et al. A whole-genome association study of major determinants for host control of HIV-1. Science 317, 944–947 (2007).
Gao, X. et al. Effect of a single amino acid change in MHC class I molecules on the rate of progression to AIDS. N. Engl. J. Med. 344, 1668–1675 (2001).
Qi, Y. et al. KIR/HLA pleiotropism: protection against both HIV and opportunistic infections. PLoS Pathog. 2, e79 (2006).
Martin, M. P. et al. Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS. Nature Genet. 31, 429–434 (2002).
The first report showing that NK cell receptors affect the progression to AIDS.
Martin, M. P. et al. Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1. Nature Genet. 39, 733–740 (2007).
Alter, G. et al. HLA class I subtype-dependent expansion of KIR3DS1+ and KIR3DL1+ NK cells during acute human immunodeficiency virus type 1 infection. J. Virol. 83, 6798–6805 (2009).
Alter, G. et al. Evolution of innate and adaptive effector cell functions during acute HIV-1 infection. J. Infect. Dis. 195, 1452–1460 (2007).
Tomaras, G. D. et al. Initial B-cell responses to transmitted human immunodeficiency virus type 1: virion-binding immunoglobulin M (IgM) and IgG antibodies followed by plasma anti-gp41 antibodies with ineffective control of initial viremia. J. Virol. 82, 12449–12463 (2008).
Stacey, A. R. 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. 83, 3719–3733 (2009).
In this article, the cytokine storm that follows HIV-1 infection was shown in a plasma donor cohort in which samples were available before and during the earliest stages of infection.
Raffatellu, M. et al. Simian immunodeficiency virus-induced mucosal interleukin-17 deficiency promotes Salmonella dissemination from the gut. Nature Med. 14, 421–428 (2008).
Nilsson, J. et al. Early immune activation in gut-associated and peripheral lymphoid tissue during acute HIV infection. AIDS 21, 565–574 (2007).
Lapenta, C. et al. Type I interferon is a powerful inhibitor of in vivo HIV-1 infection and preserves human CD4+ T cells from virus-induced depletion in SCID mice transplanted with human cells. Virology 263, 78–88 (1999).
de Jong, M. D. et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nature Med. 12, 1203–1207 (2006).
Cameron, M. J. et al. Interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome. J. Virol. 81, 8692–8706 (2007).
Killian, M. S., Fujimura, S. H., Hecht, F. M. & Levy, J. A. Similar changes in plasmacytoid dendritic cell and CD4 T-cell counts during primary HIV-1 infection and treatment. AIDS 20, 1247–1252 (2006).
Malleret, B. et al. Primary infection with simian immunodeficiency virus: plasmacytoid dendritic cell homing to lymph nodes, type I interferon, and immune suppression. Blood 112, 4598–4608 (2008).
Lore, K. et al. Accumulation of DC-SIGN+CD40+ dendritic cells with reduced CD80 and CD86 expression in lymphoid tissue during acute HIV-1 infection. AIDS 16, 683–692 (2002).
Beignon, A. S. et al. Endocytosis of HIV-1 activates plasmacytoid dendritic cells via Toll-like receptor-viral RNA interactions. J. Clin. Invest. 115, 3265–3275 (2005).
Granelli-Piperno, A., Golebiowska, A., Trumpfheller, C., Siegal, F. P. & Steinman, R. M. HIV-1-infected monocyte-derived dendritic cells do not undergo maturation but can elicit IL-10 production and T cell regulation. Proc. Natl Acad. Sci. USA 101, 7669–7674 (2004).
Boasso, A. et al. HIV inhibits CD4+ T-cell proliferation by inducing indoleamine 2, 3-dioxygenase in plasmacytoid dendritic cells. Blood 109, 3351–3359 (2007).
Manches, O. et al. HIV-activated human plasmacytoid DCs induce Tregs through an indoleamine 2, 3-dioxygenase-dependent mechanism. J. Clin. Invest. 118, 3431–3439 (2008).
Sabado, R. L. et al. In vitro priming recapitulates in vivo HIV-1 specific T cell responses, revealing rapid loss of virus reactive CD4+ T cells in acute HIV-1 infection. PLoS ONE. 4, e4256 (2009).
Borrow, P. & Bhardwaj, N. Innate immune responses in primary HIV-1 infection. Curr. Opin. HIV AIDS 3, 36–44 (2008).
Clay, C. C. et al. Neuroinvasion of fluorescein-positive monocytes in acute simian immunodeficiency virus infection. J. Virol. 81, 12040–12048 (2007).
Ward, J. et al. HIV modulates the expression of ligands important in triggering natural killer cell cytotoxic responses on infected primary T-cell blasts. Blood 110, 1207–1214 (2007).
Goonetilleke, N. 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. 206, 1253–1272 (2009).
This paper shows that the first HIV-1-specific CD8+ T cells make an important contribution to the control of viraemia in acute HIV-1 infection.
Cooper, M. A. et al. Cytokine-induced memory-like natural killer cells. Proc. Natl Acad. Sci. USA 106, 1915–1919 (2009).
Sun, J. C., Beilke, J. N. & Lanier, L. L. Adaptive immune features of natural killer cells. Nature 457, 557–561 (2009).
Cummins, J. E. Jr & Doncel, G. F. Biomarkers of cervicovaginal inflammation for the assessment of microbicide safety. Sex. Transm. Dis. 36, S84–S91 (2009).
Li, Q. et al. Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells. Nature 434, 1148–1152 (2005).
Mueller, Y. M. et al. IL-15 treatment during acute simian immunodeficiency virus (SIV) infection increases viral set point and accelerates disease progression despite the induction of stronger SIV-specific CD8+ T cell responses. J. Immunol. 180, 350–360 (2008).
Pantaleo, G. et al. Major expansion of CD8+ T cells with a predominant Vβ usage during the primary immune response to HIV. Nature 370, 463–467 (1994).
Fiebig, E. W. et al. Dynamics of HIV viremia and antibody seroconversion in plasma donors: implications for diagnosis and staging of primary HIV infection. AIDS 17, 1871–1879 (2003).
Bernardin, F., Kong, D., Peddada, L., Baxter-Lowe, L. A. & Delwart, E. Human immunodeficiency virus mutations during the first month of infection are preferentially found in known cytotoxic T-lymphocyte epitopes. J. Virol. 79, 11523–11528 (2005).
Draenert, R. et al. Immune selection for altered antigen processing leads to cytotoxic T lymphocyte escape in chronic HIV-1 infection. J. Exp. Med. 199, 905–915 (2004).
Jones, N. A. et al. Determinants of human immunodeficiency virus type 1 escape from the primary CD8+ cytotoxic T lymphocyte response. J. Exp. Med. 200, 1243–1256 (2004).
Tenzer, S. et al. Antigen processing influences HIV-specific cytotoxic T lymphocyte immunodominance. Nature Immunol. 10, 636–646 (2009).
Turnbull, E. L. et al. Kinetics of expansion of epitope-specific T cell responses during primary HIV-1 infection. J. Immunol. 182, 7131–7145 (2009).
Wang, Y. E. et al. Protective HLA class I alleles that restrict acute-phase CD8+ T-cell responses are associated with viral escape mutations located in highly conserved regions of human immunodeficiency virus type 1. J. Virol. 83, 1845–1855 (2009).
Streeck, H. et al. Human immunodeficiency virus type 1-specific CD8+ T-cell responses during primary infection are major determinants of the viral set point and loss of CD4+ T cells. J. Virol. 83, 7641–7648 (2009).
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. 205, 1009–1017 (2008).
Koup, R. A. Virus escape from CTL recognition. J. Exp. Med. 180, 779–782 (1994).
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. Nature Med. 3, 205–211 (1997).
O'Connor, D. H. et al. Acute phase cytotoxic T lymphocyte escape is a hallmark of simian immunodeficiency virus infection. Nature Med. 8, 493–499 (2002).
Leslie, A. J. et al. HIV evolution: CTL escape mutation and reversion after transmission. Nature Med. 10, 282–289 (2004).
This report describes the reversion of virus sequence in the absence of HLA-specific selective immune pressure.
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. 79, 13239–13249 (2005).
Fernandez, C. S. et al. Rapid viral escape at an immunodominant simian-human immunodeficiency virus cytotoxic T-lymphocyte epitope exacts a dramatic fitness cost. J. Virol. 79, 5721–5731 (2005).
Martinez-Picado, J. et al. Fitness cost of escape mutations in p24 Gag in association with control of human immunodeficiency virus type 1. J. Virol. 80, 3617–3623 (2006).
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. 81, 12382–12393 (2007).
Brumme, Z. L. et al. Marked epitope- and allele-specific differences in rates of mutation in human immunodeficiency type 1 (HIV-1) Gag, Pol, and Nef cytotoxic T-lymphocyte epitopes in acute/early HIV-1 infection. J. Virol. 82, 9216–9227 (2008).
Asquith, B., Edwards, C. T., Lipsitch, M. & McLean, A. R. Inefficient cytotoxic T lymphocyte-mediated killing of HIV-1-infected cells in vivo. PLoS Biol. 4, e90 (2006).
A mathematical model that describes the relationship between T cell killing, viral fitness and the rate of virus escape.
Crawford, H. et al. Compensatory mutation partially restores fitness and delays reversion of escape mutation within the immunodominant HLA-B*5703-restricted Gag epitope in chronic human immunodeficiency virus type 1 infection. J. Virol. 81, 8346–8351 (2007).
Addo, M. M. et al. Comprehensive epitope analysis of human immunodeficiency virus type 1 (HIV-1)-specific T-cell responses directed against the entire expressed HIV-1 genome demonstrate broadly directed responses, but no correlation to viral load. J. Virol. 77, 2081–2092 (2003).
Douek, D. C. et al. HIV preferentially infects HIV-specific CD4+ T cells. Nature 417, 95–98 (2002).
Pitcher, C. J. et al. HIV-1-specific CD4+ T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression. Nature Med. 5, 518–525 (1999).
Kaufmann, D. E. et al. Comprehensive analysis of human immunodeficiency virus type 1-specific CD4 responses reveals marked immunodominance of gag and nef and the presence of broadly recognized peptides. J. Virol. 78, 4463–4477 (2004).
Oxenius, A. et al. Variable fate of virus-specific CD4+ T cells during primary HIV-1 infection. Eur. J. Immunol. 31, 3782–3788 (2001).
Gloster, S. E. et al. Association of strong virus-specific CD4 T cell responses with efficient natural control of primary HIV-1 infection. AIDS 18, 749–755 (2004).
Rosenberg, E. S. et al. Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 278, 1447–1450 (1997).
Oxenius, A. et al. Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of CD8+ and CD4+ T lymphocytes. Proc. Natl Acad. Sci. USA 97, 3382–3387 (2000).
Sun, J. C., Williams, M. A. & Bevan, M. J. CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection. Nature Immunol. 5, 927–933 (2004).
Champagne, P. et al. Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 410, 106–111 (2001).
Streeck, H., van Bockel, D. & Kelleher, A. T-cell responses in primary HIV-1 infection. Curr. Opin. HIV AIDS 3, 52–59 (2008).
Liu, J. et al. Immune control of an SIV challenge by a T-cell-based vaccine in rhesus monkeys. Nature 457, 87–91 (2009).
Dong, T. et al. HIV-specific cytotoxic T cells from long-term survivors select a unique T cell receptor. J. Exp. Med. 200, 1547–1557 (2004).
Turnbull, E. L. et al. HIV-1 epitope-specific CD8+ T cell responses strongly associated with delayed disease progression cross-recognize epitope variants efficiently. J. Immunol. 176, 6130–6146 (2006).
Wei, X. et al. Antibody neutralization and escape by HIV-1. Nature 422, 307–312 (2003).
The timing of the first antibody-selected escape mutations of HIV-1 in acute infection highlights the role of the glycan shield.
Richman, D. D., Wrin, T., Little, S. J. & Petropoulos, C. J. Rapid evolution of the neutralizing antibody response to HIV type 1 infection. Proc. Natl Acad. Sci. USA 100, 4144–4149 (2003).
This study shows that neutralizing antibodies account for the extensive variation in the HIV-1 Env proteins observed in the early months of primary infection.
Gray, E. S. et al. Neutralizing antibody responses in acute human immunodeficiency virus type 1 subtype C infection. J. Virol. 81, 6187–6196 (2007).
Stamatatos, L., Morris, L., Burton, D. R. & Mascola, J. R. Neutralizing antibodies generated during natural HIV-1 infection: good news for an HIV-1 vaccine? Nature Med. 15, 866–870 (2009).
Gray, E. S. et al. Broad neutralization of human immunodeficiency virus type 1 mediated by plasma antibodies against the gp41 membrane proximal external region. J. Virol. 83, 11265–11274 (2009).
Derdeyn, C. A. et al. Envelope-constrained neutralization-sensitive HIV-1 after heterosexual transmission. Science 303, 2019–2022 (2004).
Alam, S. M. et al. The role of antibody polyspecificity and lipid reactivity in binding of broadly neutralizing anti-HIV-1 envelope human monoclonal antibodies 2F5 and 4E10 to glycoprotein 41 membrane proximal envelope epitopes. J. Immunol. 178, 4424–4435 (2007).
Alam, S. M. et al. Human immunodeficiency virus type 1 gp41 antibodies that mask membrane proximal region epitopes: antibody binding kinetics, induction, and potential for regulation in acute infection. J. Virol. 82, 115–125 (2008).
Crooks, E. T. et al. A comparative immunogenicity study of HIV-1 virus-like particles bearing various forms of envelope proteins, particles bearing no envelope and soluble monomeric gp120. Virology 366, 245–262 (2007).
Tobin, G. J. et al. Deceptive imprinting and immune refocusing in vaccine design. Vaccine 26, 6189–6199 (2008).
Forthal, D. N., Landucci, G. & Daar, E. S. Antibody from patients with acute human immunodeficiency virus (HIV) infection inhibits primary strains of HIV type 1 in the presence of natural-killer effector cells. J. Virol. 75, 6953–6961 (2001).
Aasa-Chapman, M. M. et al. Detection of antibody-dependent complement-mediated inactivation of both autologous and heterologous virus in primary human immunodeficiency virus type 1 infection. J. Virol. 79, 2823–2830 (2005).
Burrer, R., Haessig-Einius, S., Aubertin, A. M. & Moog, C. Neutralizing as well as non-neutralizing polyclonal immunoglobulin (Ig)G from infected patients capture HIV-1 via antibodies directed against the principal immunodominant domain of gp41. Virology 333, 102–113 (2005).
Moore, P. L. et al. The c3-v4 region is a major target of autologous neutralizing antibodies in human immunodeficiency virus type 1 subtype C infection. J. Virol. 82, 1860–1869 (2008).
Calarese, D. A. et al. Antibody domain exchange is an immunological solution to carbohydrate cluster recognition. Science 300, 2065–2071 (2003).
Kwong, P. D. et al. HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites. Nature 420, 678–682 (2002).
This report shows that conformational masking enables HIV-1 to maintain receptor binding and simultaneously resist antibody-mediated neutralization.
Ofek, G. et al. Structure and mechanistic analysis of the anti-human immunodeficiency virus type 1 antibody 2F5 in complex with its gp41 epitope. J. Virol. 78, 10724–10737 (2004).
Cardoso, R. M. et al. Structural basis of enhanced binding of extended and helically constrained peptide epitopes of the broadly neutralizing HIV-1 antibody 4E10. J. Mol. Biol. 365, 1533–1544 (2007).
Nelson, J. D. 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. 81, 4033–4043 (2007).
Shen, X. et al. In vivo gp41 antibodies targeting the 2F5 monoclonal antibody epitope mediate human immunodeficiency virus type 1 neutralization breadth. J. Virol. 83, 3617–3625 (2009).
Haynes, B. F., Moody, M. A., Verkoczy, L., Kelsoe, G. & Alam, S. M. Antibody polyspecificity and neutralization of HIV-1: a hypothesis. Hum. Antibodies 14, 59–67 (2005).
Fox, C. H. et al. Lymphoid germinal centers are reservoirs of human immunodeficiency virus type 1 RNA. J. Infect. Dis. 164, 1051–1057 (1991).
Pantaleo, G. et al. Lymphoid organs function as major reservoirs for human immunodeficiency virus. Proc. Natl Acad. Sci. USA 88, 9838–9842 (1991).
Muro-Cacho, C. A., Pantaleo, G. & Fauci, A. S. Analysis of apoptosis in lymph nodes of HIV-infected persons. Intensity of apoptosis correlates with the general state of activation of the lymphoid tissue and not with stage of disease or viral burden. J. Immunol. 154, 5555–5566 (1995).
Zhang, Z. Q. et al. Early depletion of proliferating B cells of germinal center in rapidly progressive simian immunodeficiency virus infection. Virology 361, 455–464 (2007).
Mascola, J. R. et al. Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies. Nature Med. 6, 207–210 (2000).
An important study that showed that neutralizing antibodies can protect against mucosal transmission, thus providing a rationale for vaccine strategies aimed at eliciting these antibodies.
Hessell, A. J. et al. Fc receptor but not complement binding is important in antibody protection against HIV. Nature 449, 101–104 (2007).
Hessell, A. J. et al. Effective, low-titer antibody protection against low-dose repeated mucosal SHIV challenge in macaques. Nature Med. 15, 951–954 (2009).
An elegant study addressing the level of antibody needed at mucosal sites for protection, which can inform experimental vaccine evaluation on the protocol needed for sufficient elicitation of antibodies.
Hessell, A. J. 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. 5, e1000433 (2009).
Engram, J. C. et al. Vaccine-induced, simian immunodeficiency virus-specific CD8+ T cells reduce virus replication but do not protect from simian immunodeficiency virus disease progression. J. Immunol. 183, 706–717 (2009).
Rerks-Ngarm, S. et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N. Engl. J. Med. 20 Oct 2009 (doi:10.1056/NEJMoa0908492).
Reynolds, M. R. et al. Macaques vaccinated with live-attenuated SIV control replication of heterologous virus. J. Exp. Med. 205, 2537–2550 (2008).
Althaus, C. L. & De Boer, R. J. Dynamics of immune escape during HIV/SIV infection. PLoS Comput. Biol. 4, e1000103 (2008).
Lee, J. K. et al. T cell cross-reactivity and conformational changes during TCR engagement. J. Exp. Med. 200, 1455–1466 (2004).
Santra, S. et al. A centralized gene-based HIV-1 vaccine elicits broad cross-clade cellular immune responses in rhesus monkeys. Proc. Natl Acad. Sci. USA 105, 10489–10494 (2008).
Barouch, D. & Korber, B. HIV-1 mosaic antigens expand cellular immune breadth and depth in rhesus monkeys. Abstr. S06-04 AIDS vaccine conference 2009, Paris (2009)
Korber, B., Gnankaran, S. & Perkins, S. New applications for mosaic antigen designs. Abstr. S06-03 AIDS vaccine conference 2009, Paris (2009)
Pitisuttithum, P. et al. Randomized, double-blind, placebo-controlled efficacy trial of a bivalent recombinant glycoprotein 120 HIV-1 vaccine among injection drug users in Bangkok, Thailand. J. Infect. Dis. 194, 1661–1671 (2006).
McElrath, M. J. et al. HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case-cohort analysis. Lancet 372, 1894–1905 (2008).
Buchbinder, S. P. et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet 372, 1881–1893 (2008).
Casimiro, D. R. et al. Attenuation of simian immunodeficiency virus SIVmac239 infection by prophylactic immunization with dna and recombinant adenoviral vaccine vectors expressing Gag. J. Virol. 79, 15547–15555 (2005).
Hansen, S. G. et al. Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge. Nature Med. 15, 293–299 (2009).
Walker, B. D. & Burton, D. R. Toward an AIDS vaccine. Science 320, 760–764 (2008).
Baker, B. M., Block, B. L., Rothchild, A. C. & Walker, B. D. Elite control of HIV infection: implications for vaccine design. Expert Opin. Biol. Ther. 9, 55–69 (2009).
Wong, S. B. J. & Siliciano, R. F. in AIDS Vaccine Development: Challenges and Opportunities (eds. Koff, W. C., Kahn, P. & Gust, I. D.) 17–22 (Caister Academic, UK, 2007).