Abstract
Despite limited data supporting the superiority of dominant over subdominant responses, immunodominant epitopes represent the preferred vaccine candidates. To address the function of subdominant responses in human immunodeficiency virus infection, we analyzed cytotoxic T lymphocyte responses restricted by HLA-B*1503, a rare allele in a cohort infected with clade B, although common in one infected with clade C. HLA-B*1503 was associated with reduced viral loads in the clade B cohort but not the clade C cohort, although both shared the immunodominant response. Clade B viral control was associated with responses to several subdominant cytotoxic T lymphocyte epitopes, whereas their clade C variants were less well recognized. These data suggest that subdominant responses can contribute to in vivo viral control and that high HLA allele frequencies may drive the elimination of subdominant yet effective epitopes from circulating viral populations.
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References
Hanke, T. et al. Effective induction of simian immunodeficiency virus-specific cytotoxic T lymphocytes in macaques by using a multiepitope gene and DNA prime-modified vaccinia virus Ankara boost vaccination regimen. J. Virol. 73, 7524–7532 (1999).
Hanke, T. & McMichael, A. Pre-clinical development of a multi-CTL epitope-based DNA prime MVA boost vaccine for AIDS. Immunol. Lett. 66, 177–181 (1999).
Wilson, C.C. et al. Development of a DNA vaccine designed to induce cytotoxic T lymphocyte responses to multiple conserved epitopes in HIV-1. J. Immunol. 171, 5611–5623 (2003).
Goulder, P.J. et al. Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nat. Med. 3, 212–217 (1997).
Feeney, M.E. et al. Immune escape precedes breakthrough human immunodeficiency virus type 1 viremia and broadening of the cytotoxic T-lymphocyte response in an HLA-B27-positive long-term-nonprogressing child. J. Virol. 78, 8927–8930 (2004).
Leslie, A.J. et al. HIV evolution: CTL escape mutation and reversion after transmission. Nat. Med. 10, 282–289 (2004).
Scherer, A. et al. Quantifiable cytotoxic T lymphocyte responses and HLA-related risk of progression to AIDS. Proc. Natl. Acad. Sci. USA 101, 12266–12270 (2004).
Brander, C. & Walker, B.D. Gradual adaptation of HIV to human host populations: good or bad news? Nat. Med. 9, 1359–1362 (2003).
Goulder, P.J. & Watkins, D.I. HIV and SIV CTL escape: implications for vaccine design. Nat. Rev. Immunol. 4, 630–640 (2004).
Trachtenberg, E. et al. Advantage of rare HLA supertype in HIV disease progression. Nat. Med. 9, 928–935 (2003).
Kiepiela, P. et al. Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA. Nature 432, 769–775 (2004).
Frahm, N. et al. Consistent cytotoxic-T-lymphocyte targeting of immunodominant regions in human immunodeficiency virus across multiple ethnicities. J. Virol. 78, 2187–2200 (2004).
Cao, K. et al. Analysis of the frequencies of HLA-A, B, and C alleles and haplotypes in the five major ethnic groups of the United States reveals high levels of diversity in these loci and contrasting distribution patterns in these populations. Hum. Immunol. 62, 1009–1030 (2001).
Frahm, N., Goulder, P.J.R. & Brander, C. Broad HIV-1 specific CTL responses reveal extensive HLA class I binding promiscuity of HIV-derived, optimally defined CTL epitopes. in HIV Immunology and HIV/SIV Vaccine Databases 2003, Vol. 1 (eds. Korber, B.T. et al.) 3–24 (Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, 2003).
Rammensee, H., Bachmann, J., Emmerich, N.P., Bachor, O.A. & Stevanovic, S. SYFPEITHI: database for MHC ligands and peptide motifs. Immunogenetics 50, 213–219 (1999).
Frahm, N., Korber, B.T. & Brander, C. Optimal CTL epitope identification in HIV clade B and non-clade B infection. in HIV Immunology and HIV/SIV Vaccine Databases 2004 (eds. Korber, B.T. et al.) (Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, in the press).
Prilliman, K.R. et al. HLA-B15 peptide ligands are preferentially anchored at their C termini. J. Immunol. 162, 7277–7284 (1999).
O'Brien, S.J., Gao, X. & Carrington, M. HLA and AIDS: a cautionary tale. Trends Mol. Med. 7, 379–381 (2001).
Flores-Villanueva, P.O. et al. Control of HIV-1 viremia and protection from AIDS are associated with HLA-Bw4 homozygosity. Proc. Natl. Acad. Sci. USA 98, 5140–5145 (2001).
Trachtenberg, E.A. & Erlich, H.A. A review of the role of the human leukocyte antigen (HLA) system as a host immunogenic factor influencing HIV transmission and progression to AIDS. in HIV Molecular Immunology 2001 (eds. Korber, B.T.K. et al.) I-43–60 (Theoretical Biology and Biophysics Group, Los Alamos, New Mexico, 2001).
Goulder, P.J. et al. Evolution and transmission of stable CTL escape mutations in HIV infection. Nature 412, 334–338 (2001).
Kelleher, A.D. et al. Clustered mutations in HIV-1 gag are consistently required for escape from HLA-B27-restricted cytotoxic T lymphocyte responses. J. Exp. Med. 193, 375–386 (2001).
Moore, C.B. et al. Evidence of HIV-1 adaptation to HLA-restricted immune responses at a population level. Science 296, 1439–1443 (2002).
Leslie, A. et al. Transmission and accumulation of CTL escape variants drive negative associations between HIV polymorphisms and HLA. J. Exp. Med. 201, 891–902 (2005).
Voeten, J.T. et al. Antigenic drift in the influenza A virus (H3N2) nucleoprotein and escape from recognition by cytotoxic T lymphocytes. J. Virol. 74, 6800–6807 (2000).
Kijak, G.H. et al. Lost in translation: implications of HIV-1 codon usage for immune escape and drug resistance. AIDS Rev. 6, 54–60 (2004).
Messaoudi, I., Guevara Patino, J.A., Dyall, R., LeMaoult, J. & Nikolich-Zugich, J. Direct link between MHC polymorphism, T cell avidity, and diversity in immune defense. Science 298, 1797–1800 (2002).
McMichael, A. & Klenerman, P. HIV/AIDS. HLA leaves its footprints on HIV. Science 296, 1410–1411 (2002).
Bunce, M. et al. Phototyping: comprehensive DNA typing for HLA-A, B, C, DRB1, DRB3, DRB4, DRB5 & DQB1 by PCR with 144 primer mixes utilizing sequence- specific primers (PCR-SSP). Tissue Antigens 46, 355–367 (1995).
Goulder, P.J. et al. Rapid definition of five novel HLA-A*3002-restricted human immunodeficiency virus-specific cytotoxic T-lymphocyte epitopes by Elispot and intracellular cytokine staining assays. J. Virol. 75, 1339–1347 (2001).
Korber, B. et al. (eds.). HIV Molecular Immunology Database 2001 (Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, 2001).
Addo, M.M. et al. Comprehensive epitope analysis of 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).
Acknowledgements
We thank P. D'Souza for discussions and guidance; the HIV Pathogenesis Program in Durban, especially N. Mngquandaniso, D. Ramduth, P. Chetty, N. Nene, N. Ntumba and C. Thobakgale, for their help in obtaining and processing samples from clade C–infected subjects; and N. Rizzo for the comparison of clade B and clade C peptides. Supported by the National Institutes of Health (N01-Al-15422, NO1-CO-12400 and R01-A1-067077) and by Los Alamos National Laboratory (la-ur-03-5892). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the US government.
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Frahm, N., Kiepiela, P., Adams, S. et al. Control of human immunodeficiency virus replication by cytotoxic T lymphocytes targeting subdominant epitopes. Nat Immunol 7, 173–178 (2006). https://doi.org/10.1038/ni1281
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DOI: https://doi.org/10.1038/ni1281
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