Background Very little is known about the immunodominance patterns of HIV-1-specific T cell responses during primary HIV-1 infection and the reasons for human lymphocyte antigen (HLA) modulation of disease progression. Methods and Findings In a cohort of 104 individuals with primary HIV-1 infection, we demonstrate that a subset of CD8+ T cell epitopes within HIV-1 are consistently targeted early after infection, while other epitopes subsequently targeted through the same HLA class I alleles are rarely recognized. Certain HLA alleles consistently contributed more than others to the total virus-specific CD8+ T cell response during primary infection, and also reduced the absolute magnitude of responses restricted by other alleles if coexpressed in the same individual, consistent with immunodomination. Furthermore, individual HLA class I alleles that have been associated with slower HIV-1 disease progression contributed strongly to the total HIV-1-specific CD8+ T cell response during primary infection. Conclusions These data demonstrate consistent immunodominance patterns of HIV-1-specific CD8+ T cell responses during primary infection and provide a mechanistic explanation for the protective effect of specific HLA class I alleles on HIV-1 disease progression.
References
[1]
Kahn JO, Walker BD (1998) Acute human immunodeficiency virus type 1 infection. N Engl J Med 339: 33–39.
[2]
Hecht FM, Busch MP, Rawal B, Webb M, Rosenberg E, et al. (2002) Use of laboratory tests and clinical symptoms for identification of primary HIV infection. AIDS 16: 1119–1129.
[3]
Koup RA, Safrit JT, Cao Y, Andrews CA, McLeod G, et al. (1994) 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.
[4]
Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MB (1994) 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.
[5]
Jin X, Bauer DE, Tuttleton SE, Lewin S, Gettie A, et al. (1999) Dramatic rise in plasma viremia after CD8+ T cell depletion in simian immunodeficiency virus-infected macaques. J Exp Med 189: 991–998.
[6]
Schmitz JE, Kuroda MJ, Santra S, Sasseville VG, Simon MA, et al. (1999) Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 283: 857–860.
[7]
Matano T, Shibata R, Siemon C, Connors M, Lane HC, et al. (1998) Administration of an anti-CD8 monoclonal antibody interferes with the clearance of chimeric simian/human immunodeficiency virus during primary infections of rhesus macaques. J Virol 72: 164–169.
[8]
Allen TM, O'Connor DH, Jing P, Dzuris JL, Mothe BR, et al. (2000) Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia. Nature 407: 386–390.
[9]
Allen TM, Altfeld M, Geer SC, Kalife ET, Moore C, et al. (2005) 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.
[10]
O'Connor DH, Allen TM, Vogel TU, Jing P, DeSouza IP, et al. (2002) Acute phase cytotoxic T lymphocyte escape is a hallmark of simian immunodeficiency virus infection. Nat Med 8: 493–499.
[11]
Jones NA, Wei X, Flower DR, Wong M, Michor F, et al. (2004) Determinants of human immunodeficiency virus type 1 escape from the primary CD8+ cytotoxic T lymphocyte response. J Exp Med 200: 1243–1256.
[12]
Altfeld M, Rosenberg ES, Shankarappa R, Mukherjee JS, Hecht FM, et al. (2001) Cellular immune responses and viral diversity in individuals treated during acute and early HIV-1 infection. J Exp Med 193: 169–180.
[13]
Cao J, McNevin J, Holte S, Fink L, Corey L, et al. (2003) Comprehensive analysis of human immunodeficiency virus type 1 (HIV-1)-specific gamma interferon-secreting CD8+ T cells in primary HIV-1 infection. J Virol 77: 6867–6878.
[14]
Dalod M, Dupuis M, Deschemin JC, Goujard C, Deveau C, et al. (1999) Weak anti-HIV CD8+ T-cell effector activity in HIV primary infection. J Clin Invest 104: 1431–1439.
[15]
Oxenius A, Price DA, Easterbrook PJ, O'Callaghan CA, Kelleher AD, et al. (2000) Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of CD8+ and CD4+ T lymphocytes. Proc Natl Acad Sci U S A 97: 3382–3387.
[16]
Migueles SA, Laborico AC, Shupert WL, Sabbaghian MS, Rabin R, et al. (2002) HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nat Immunol 3: 1061–1068.
[17]
Lichterfeld M, Yu XG, Waring MT, Mui SK, Johnston MN, et al. (2004) HIV-1-specific cytotoxicity is preferentially mediated by a subset of CD8+ T cells producing both interferon-gamma and tumor necrosis factor-alpha. Blood 104: 487–494.
[18]
Lichterfeld M, Kaufmann DE, Yu XG, Mui SK, Addo MM, et al. (2004) Loss of HIV-1-specific CD8+ T cell proliferation after acute HIV-1 infection and restoration by vaccine-induced HIV-1-specific CD4+ T cells. J Exp Med 200: 701–712.
[19]
Lieberman J, Shankar P, Manjunath N, Andersson J (2001) Dressed to kill? A review of why antiviral CD8 T lymphocytes fail to prevent progressive immunodeficiency in HIV-1 infection. Blood 98: 1667–1677.
[20]
Pantaleo G, Koup RA (2004) Correlates of immune protection in HIV-1 infection: What we know, what we don't know, what we should know. Nat Med 10: 806–810.
[21]
Goulder PJ, Altfeld MA, Rosenberg ES, Nguyen T, Tang Y, et al. (2001) Substantial differences in specificity of HIV-specific cytotoxic T cells in acute and chronic HIV infection. J Exp Med 193: 181–194.
[22]
Yu XG, Addo MM, Rosenberg ES, Rodriguez WR, Lee PK, et al. (2002) Consistent patterns in the development and immunodominance of human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T-cell responses following acute HIV-1 Infection. J Virol 76: 8690–8701.
[23]
Altfeld M, Addo MM, Rosenberg ES, Hecht FM, Lee PK, et al. (2003) Influence of HLA-B57 on clinical presentation and viral control during acute HIV-1 infection. AIDS 17: 2581–2591.
[24]
Allen TM, Altfeld M, Yu XG, O'Sullivan KM, Lichterfeld M, et al. (2004) Selection, transmission, and reversion of an antigen-processing cytotoxic T-lymphocyte escape mutation in human immunodeficiency virus type 1 infection. J Virol 78: 7069–7078.
[25]
Cao J, McNevin J, Malhotra U, McElrath MJ (2003) Evolution of CD8+ T cell immunity and viral escape following acute HIV-1 infection. J Immunol 171: 3837–3846.
[26]
Brander C, Goulder P (2000) The evolving field of HIV CRL epitope mapping: New approaches for the identification of novel epitopes. In: Korber BTM, Brander C, Walker BD, Koup RA, Moore J, et al., editors. HIV molecular database. Los Alamos (New Mexico): Los Alamos National Laboratory.
[27]
Carrington M, Nelson GW, Martin MP, Kissner T, Vlahov D, et al. (1999) HLA and HIV-1: Heterozygote advantage and B*35-Cw*04 disadvantage. Science 283: 1748–1752.
[28]
O'Brien SJ, Gao X, Carrington M (2001) HLA and AIDS: A cautionary tale. Trends Mol Med 7: 379–381.
[29]
Gao X, Bashirova A, Iversen AK, Phair J, Goedert JJ, et al. (2005) AIDS restriction HLA allotypes target distinct intervals of HIV-1 pathogenesis. Nat Med 11: 1290–1292.
[30]
Gao X, Nelson GW, Karacki P, Martin MP, Phair J, et al. (2001) 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.
[31]
Kiepiela P, Leslie AJ, Honeyborne I, Ramduth D, Thobakgale C, et al. (2004) Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA. Nature 432: 769–775.
[32]
Altfeld M, Allen TM, Kalife ET, Frahm N, Addo MM, et al. (2005) The majority of currently circulating human immunodeficiency virus type 1 clade B viruses fail to prime cytotoxic T-lymphocyte responses against an otherwise immunodominant HLA-A2-restricted epitope: Implications for vaccine design. J Virol 79: 5000–5005.
[33]
Goulder PJ, Brander C, Tang Y, Tremblay C, Colbert RA, et al. (2001) Evolution and transmission of stable CTL escape mutations in HIV infection. Nature 412: 334–338.
[34]
Altfeld M, Addo MM, Shankarappa R, Lee PK, Allen TM, et al. (2003) Enhanced detection of human immunodeficiency virus type 1-specific T-cell responses to highly variable regions by using peptides based on autologous virus sequences. J Virol 77: 7330–7340.
[35]
Yusim K, Kesmir C, Gaschen B, Addo MM, Altfeld M, et al. (2002) Clustering patterns of cytotoxic T-lymphocyte epitopes in human immunodeficiency virus type 1 (HIV-1) proteins reveal imprints of immune evasion on HIV-1 global variation. J Virol 76: 8757–8768.
[36]
Kaslow RA, Rivers C, Tang J, Bender TJ, Goepfert PA, et al. (2001) Polymorphisms in HLA class I genes associated with both favorable prognosis of human immunodeficiency virus (HIV) type 1 infection and positive cytotoxic T-lymphocyte responses to ALVAC-HIV recombinant canarypox vaccines. J Virol 75: 8681–8689.
[37]
Kaslow RA, Carrington M, Apple R, Park L, Munoz A, et al. (1996) Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection. Nat Med 2: 405–411.
[38]
Yewdell JW, Bennink JR (1999) Immunodominance in major histocompatibility complex class I-restricted T lymphocyte responses. Annu Rev Immunol 17: 51–88.
[39]
Yewdell JW, Del Val M (2004) Immunodominance in TCD8+ responses to viruses: Cell biology, cellular immunology, and mathematical models. Immunity 21: 149–153.
[40]
Sherritt MA, Gardner J, Elliott SL, Schmidt C, Purdie D, et al. (2000) Effect of pre-existing cytotoxic T lymphocytes on therapeutic vaccines. Eur J Immunol 30: 671–677.
[41]
Roy-Proulx G, Meunier MC, Lanteigne AM, Brochu S, Perreault C (2001) Immunodomination results from functional differences between competing CTL. Eur J Immunol 31: 2284–2292.
[42]
van der Most RG, Harrington LE, Giuggio V, Mahar PL, Ahmed R (2002) Yellow fever virus 17D envelope and NS3 proteins are major targets of the antiviral T cell response in mice. Virology 296: 117–124.
[43]
Chen W, Pang K, Masterman KA, Kennedy G, Basta S, et al. (2004) Reversal in the immunodominance hierarchy in secondary CD8+ T cell responses to influenza A virus: Roles for cross-presentation and lysis-independent immunodomination. J Immunol 173: 5021–5027.
[44]
Roy-Proulx G, Baron C, Perreault C (2005) CD8 T-cell ability to exert immunodomination correlates with T-cell receptor: Epitope association rate. Biol Blood Marrow Transplant 11: 260–271.
[45]
van der Most RG, Concepcion RJ, Oseroff C, Alexander J, Southwood S, et al. (1997) Uncovering subdominant cytotoxic T-lymphocyte responses in lymphocytic choriomeningitis virus-infected BALB/c mice. J Virol 71: 5110–5114.
[46]
Hollsberg P (2002) Contribution of HLA class I allele expression to CD8+ T-cell responses against Epstein-Barr virus. Scand J Immunol 55: 189–195.
[47]
Lacey SF, Villacres MC, La Rosa C, Wang Z, Longmate J, et al. (2003) Relative dominance of HLA-B*07 restricted CD8+ T-lymphocyte immune responses to human cytomegalovirus pp65 in persons sharing HLA-A*02 and HLA-B*07 alleles. Hum Immunol 64: 440–452.
[48]
Newberg MH, McEvers KJ, Gorgone DA, Lifton MA, Baumeister SH, et al. (2006) Immunodomination in the evolution of dominant epitope-specific CD8+ T lymphocyte responses in simian immunodeficiency virus-infected rhesus monkeys. J Immunol 176: 319–328.
[49]
McDermott AB, O'Connor DH, Fuenger S, Piaskowski S, Martin S, et al. (2005) Cytotoxic T-lymphocyte escape does not always explain the transient control of simian immunodeficiency virus SIVmac239 viremia in adenovirus-boosted and DNA-primed Mamu-A*01-positive rhesus macaques. J Virol 79: 15556–15566.
[50]
Seaman MS, Santra S, Newberg MH, Philippon V, Manson K, et al. (2005) Vaccine-elicited memory cytotoxic T lymphocytes contribute to Mamu-A*01-associated control of simian/human immunodeficiency virus 89.6P replication in rhesus monkeys. J Virol 79: 4580–4588.
[51]
O'Connor DH, Mothe BR, Weinfurter JT, Fuenger S, Rehrauer WM, et al. (2003) Major histocompatibility complex class I alleles associated with slow simian immunodeficiency virus disease progression bind epitopes recognized by dominant acute-phase cytotoxic-T-lymphocyte responses. J Virol 77: 9029–9040.
[52]
Mothe BR, Weinfurter J, Wang C, Rehrauer W, Wilson N, et al. (2003) Expression of the major histocompatibility complex class I molecule Mamu-A*01 is associated with control of simian immunodeficiency virus SIVmac239 replication. J Virol 77: 2736–2740.
[53]
Zhang ZQ, Fu TM, Casimiro DR, Davies ME, Liang X, et al. (2002) Mamu-A*01 allele-mediated attenuation of disease progression in simian-human immunodeficiency virus infection. J Virol 76: 12845–12854.
