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. 2010 Jul 7;1(6):514–519. doi: 10.1007/s13238-010-0068-0

Dynamic interplay between viral adaptation and immune recognition during HIV-1 infection

Chihiro Motozono 1, Philip Mwimanzi 1, Takamasa Ueno 1,✉
PMCID: PMC4875316  PMID: 21204005

Abstract

Untreated human immunodeficiency virus (HIV) infections usually lead to death from AIDS, although the rate of the disease progression varies widely among individuals. The cytotoxic T lymphocyte (CTL) response, which is restricted by highly polymorphic MHC class I alleles, plays a central role in controlling HIV replication. It is now recognized that the antiviral efficacy of CTLs at the single cell level is dependent on their antigen specificity and is important in determining the quality of host response to viruses so that the individual will remain asymptomatic. However, because of the extreme mutational plasticity of HIV, HIV-specific CTL responses are continuously and dynamically changing. In order to rationally design an effective vaccine, the questions as to what constitutes an effective antiviral CTL response and what characterizes a potent antigenic peptide to induce such responses are becoming highlighted as needing to be answered.

Keywords: HIV/AIDS, peptide-MHC complex, HLA class I, cytotoxic T lymphocyte, immune escape

References

  1. Allen T.M., Altfeld M., Geer S.C., Kalife E.T., Moore C., O’sullivan K.M., Desouza I., Feeney M.E., Eldridge R.L., Maier E.L., et al. Selective escape from CD8+ T-cell responses represents a major driving force of human immunodeficiency virus type 1 (HIV-1) sequence diversity and reveals constraints on HIV-1 evolution. J Virol. 2005;79:13239–13249. doi: 10.1128/JVI.79.21.13239-13249.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Allen T.M., Yu X.G., Kalife E.T., Reyor L.L., Lichterfeld M., John M., Cheng M., Allgaier R.L., Mui S., Frahm N., et al. De novo generation of escape variant-specific CD8+ T-cell responses following cytotoxic T-lymphocyte escape in chronic human immunodeficiency virus type 1 infection. J Virol. 2005;79:12952–12960. doi: 10.1128/JVI.79.20.12952-12960.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Apostolopoulos V., Lazoura E., Yu M. MHC and MHC-like molecules: structural perspectives on the design of molecular vaccines. Adv Exp Med Biol. 2008;640:252–267. doi: 10.1007/978-0-387-09789-3_19. [DOI] [PubMed] [Google Scholar]
  4. Appay V., Nixon D.F., Donahoe S.M., Gillespie G.M., Dong T., King A., Ogg G.S., Spiegel H.M., Conlon C., Spina C.A., et al. HIV-specific CD8(+) T cells produce antiviral cytokines but are impaired in cytolytic function. J Exp Med. 2000;192:63–75. doi: 10.1084/jem.192.1.63. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. 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. 2009;9:55–69. doi: 10.1517/14712590802571928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bangham C.R.M. CTL quality and the control of human retroviral infections. Eur J Immunol. 2009;39:1700–1712. doi: 10.1002/eji.200939451. [DOI] [PubMed] [Google Scholar]
  7. Betts M.R., Ambrozak D.R., Douek D.C., Bonhoeffer S., Brenchley J.M., Casazza J.P., Koup R.A., Picker L.J. 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. doi: 10.1128/JVI.75.24.11983-11991.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Borbulevych O.Y., Baxter T.K., Yu Z., Restifo N.P., Baker B.M. Increased immunogenicity of an anchor-modified tumor-associated antigen is due to the enhanced stability of the peptide/MHC complex: implications for vaccine design. J Immunol. 2005;174:4812–4820. doi: 10.4049/jimmunol.174.8.4812. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Borbulevych O.Y., Piepenbrink K.H., Gloor B.E., Scott D.R., Sommese R.F., Cole D.K., Sewell A.K., Baker B.M. T cell receptor cross-reactivity directed by antigen-dependent tuning of peptide-MHC molecular flexibility. Immunity. 2009;31:885–896. doi: 10.1016/j.immuni.2009.11.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. 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. 1994;68:6103–6110. doi: 10.1128/jvi.68.9.6103-6110.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Carlson J.M., Brumme Z.L. HIV evolution in response to HLA-restricted CTL selection pressures: a population-based perspective. Microbes Infect. 2008;10:455–461. doi: 10.1016/j.micinf.2008.01.013. [DOI] [PubMed] [Google Scholar]
  12. Carrington M., Nelson G.W., Martin M.P., Kissner T., Vlahov D., Goedert J.J., Kaslow R., Buchbinder S., Hoots K., O’Brien S.J. HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage. Science. 1999;283:1748–1752. doi: 10.1126/science.283.5408.1748. [DOI] [PubMed] [Google Scholar]
  13. Feeney M.E., Tang Y., Pfafferott K., Roosevelt K.A., Draenert R., Trocha A., Yu X.G., Verrill C., Allen T., Moore C., et al. HIV-1 viral escape in infancy followed by emergence of a variantspecific CTL response. J Immunol. 2005;174:7524–7530. doi: 10.4049/jimmunol.174.12.7524. [DOI] [PubMed] [Google Scholar]
  14. Goulder P.J.R., Altfeld M.A., Rosenberg E.S., Nguyen T., Tang Y., Eldridge R.L., Addo M.M., He S., Mukherjee J.S., Phillips M.N., et al. Substantial differences in specificity of HIV-specific cytotoxic T cells in acute and chronic HIV infection. J Exp Med. 2001;193:181–194. doi: 10.1084/jem.193.2.181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Goulder P.J.R., Watkins D.I. HIV and SIV CTL escape: implications for vaccine design. Nat Rev Immunol. 2004;4:630–640. doi: 10.1038/nri1417. [DOI] [PubMed] [Google Scholar]
  16. Hillig R.C., Hülsmeyer M., Saenger W., Welfle K., Misselwitz R., Welfle H., Kozerski C., Volz A., Uchanska-Ziegler B., Ziegler A. Thermodynamic and structural analysis of peptide- and allele-dependent properties of two HLA-B27 subtypes exhibiting differential disease association. J Biol Chem. 2004;279:652–663. doi: 10.1074/jbc.M307457200. [DOI] [PubMed] [Google Scholar]
  17. Hülsmeyer M., Welfle K., Pöhlmann T., Misselwitz R., Alexiev U., Welfle H., Saenger W., Uchanska-Ziegler B., Ziegler A. Thermodynamic and structural equivalence of two HLA-B27 subtypes complexed with a self-peptide. J Mol Biol. 2005;346:1367–1379. doi: 10.1016/j.jmb.2004.12.047. [DOI] [PubMed] [Google Scholar]
  18. Kosmrlj A., Read E.L., Qi Y., Allen T.M., Altfeld M., Deeks S.G., Pereyra F., Carrington M., Walker B.D., Chakraborty A.K. Effects of thymic selection of the T-cell repertoire on HLA class I-associated control of HIV infection. Nature. 2010;465:350–354. doi: 10.1038/nature08997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Koup R.A., Safrit J.T., Cao Y., Andrews C.A., McLeod G., Borkowsky W., Farthing C., Ho D.D. 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. doi: 10.1128/jvi.68.7.4650-4655.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Migueles S.A., Laborico A.C., Shupert W.L., Sabbaghian M.S., Rabin R., Hallahan C.W., Van Baarle D., Kostense S., Miedema F., McLaughlin M., et al. HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nat Immunol. 2002;3:1061–1068. doi: 10.1038/ni845. [DOI] [PubMed] [Google Scholar]
  21. Motozono C., Yanaka S., Tsumoto K., Takiguchi M., Ueno T. Impact of intrinsic cooperative thermodynamics of peptide- MHC complexes on antiviral activity of HIV-specific CTL. J Immunol. 2009;182:5528–5536. doi: 10.4049/jimmunol.0803471. [DOI] [PubMed] [Google Scholar]
  22. Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., et al. The DNA sequence and analysis of human chromosome 6. Nature. 2003;425:805–811. doi: 10.1038/nature02055. [DOI] [PubMed] [Google Scholar]
  23. O’Brien S.J., Gao X., Carrington M. HLA and AIDS: a cautionary tale. Trends Mol Med. 2001;7:379–381. doi: 10.1016/S1471-4914(01)02131-1. [DOI] [PubMed] [Google Scholar]
  24. O’Connell K.A., Bailey J.R., Blankson J.N. Elucidating the elite: mechanisms of control in HIV-1 infection. Trends Pharmacol Sci. 2009;30:631–637. doi: 10.1016/j.tips.2009.09.005. [DOI] [PubMed] [Google Scholar]
  25. Ogg G.S., Jin X., Bonhoeffer S., Dunbar P.R., Nowak M.A., Monard S., Segal J.P., Cao Y., Rowland-Jones S.L., Cerundolo V., et al. Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. Science. 1998;279:2103–2106. doi: 10.1126/science.279.5359.2103. [DOI] [PubMed] [Google Scholar]
  26. Rammensee H.G., Friede T., Stevanoviíc S. MHC ligands and peptide motifs: first listing. Immunogenetics. 1995;41:178–228. doi: 10.1007/BF00172063. [DOI] [PubMed] [Google Scholar]
  27. Rudolph M.G., Stanfield R.L., Wilson I.A. How TCRs bind MHCs, peptides, and coreceptors. Annu Rev Immunol. 2006;24:419–466. doi: 10.1146/annurev.immunol.23.021704.115658. [DOI] [PubMed] [Google Scholar]
  28. Sáez-Cirión A., Lacabaratz C., Lambotte O., Versmisse P., Urrutia A., Boufassa F., Barré-Sinoussi F., Delfraissy J.-F., Sinet M., Pancino G., the Agence Nationale de Recherches sur le Sida EP36 HIV Controllers Study Group 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. doi: 10.1073/pnas.0611244104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Shankarappa R., Margolick J.B., Gange S.J., Rodrigo A.G., Upchurch D., Farzadegan H., Gupta P., Rinaldo C.R., Learn G.H., He X., et al. Consistent viral evolutionary changes associated with the progression of human immunodeficiency virus type 1 infection. J Virol. 1999;73:10489–10502. doi: 10.1128/jvi.73.12.10489-10502.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Smith K.J., Reid S.W., Stuart D.I., McMichael A.J., Jones E.Y., Bell J.I. An altered position of the α2 helix of MHC class I is revealed by the crystal structure of HLA-B*3501. Immunity. 1996;4:203–213. doi: 10.1016/S1074-7613(00)80429-X. [DOI] [PubMed] [Google Scholar]
  31. Stewart-Jones G.B.E., Gillespie G., Overton I.M., Kaul R., Roche P., McMichael A.J., Rowland-Jones S., Jones E.Y. Structures of three HIV-1 HLA-B*5703-peptide complexes and identification of related HLAs potentially associated with long-term nonprogression. J Immunol. 2005;175:2459–2468. doi: 10.4049/jimmunol.175.4.2459. [DOI] [PubMed] [Google Scholar]
  32. Tomiyama H., Fujiwara M., Oka S., Takiguchi M. Cutting Edge: Epitope-dependent effect of Nef-mediated HLA class I down-regulation on ability of HIV-1-specific CTLs to suppress HIV-1 replication. J Immunol. 2005;174:36–40. doi: 10.4049/jimmunol.174.1.36. [DOI] [PubMed] [Google Scholar]
  33. Ueno T., Idegami Y., Motozono C., Oka S., Takiguchi M. Altering effects of antigenic variations in HIV-1 on antiviral effectiveness of HIV-specific CTLs. J Immunol. 2007;178:5513–5523. doi: 10.4049/jimmunol.178.9.5513. [DOI] [PubMed] [Google Scholar]
  34. Ueno T., Motozono C., Dohki S., Mwimanzi P., Rauch S., Fackler O.T., Oka S., Takiguchi M. CTL-mediated selective pressure influences dynamic evolution and pathogenic functions of HIV-1 Nef. J Immunol. 2008;180:1107–1116. doi: 10.4049/jimmunol.180.2.1107. [DOI] [PubMed] [Google Scholar]
  35. Ueno T., Tomiyama H., Fujiwara M., Oka S., Takiguchi M. Functionally impaired HIV-specific CD8 T cells show high affinity TCR-ligand interactions. J Immunol. 2004;173:5451–5457. doi: 10.4049/jimmunol.173.9.5451. [DOI] [PubMed] [Google Scholar]
  36. Yang O.O., Kalams S.A., Trocha A., Cao H., Luster A., Johnson R.P., Walker B.D. Suppression of human immunodeficiency virus type 1 replication by CD8+ cells: evidence for HLA class I-restricted triggering of cytolytic and noncytolytic mechanisms. J Virol. 1997;71:3120–3128. doi: 10.1128/jvi.71.4.3120-3128.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Yang O.O., Sarkis P.T.N., Trocha A., Kalams S.A., Johnson R.P., Walker B.D. Impacts of avidity and specificity on the antiviral efficiency of HIV-1-specific CTL. J Immunol. 2003;171:3718–3724. doi: 10.4049/jimmunol.171.7.3718. [DOI] [PubMed] [Google Scholar]
  38. Yewdell J.W. Confronting complexity: real-world immunodominance in antiviral CD8+ T cell responses. Immunity. 2006;25:533–543. doi: 10.1016/j.immuni.2006.09.005. [DOI] [PubMed] [Google Scholar]
  39. Yu Z., Theoret M.R., Touloukian C.E., Surman D.R., Garman S.C., Feigenbaum L., Baxter T.K., Baker B.M., Restifo N.P. Poor immunogenicity of a self/tumor antigen derives from peptide-MHC-I instability and is independent of tolerance. J Clin Invest. 2004;114:551–559. doi: 10.1172/JCI200421695. [DOI] [PMC free article] [PubMed] [Google Scholar]

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