Engendering cytotoxic T-lymphocyte (CTL) responses is likely to be an important goal of HIV vaccines. However, CTLs select for viral variants that escape immune detection. Maintenance of such escape variants in human populations could pose an obstacle to HIV vaccine development. We first observed that escape mutations in a heterogeneous simian immunodeficiency virus (SIV) isolate were lost upon passage to new animals. We therefore infected macaques with a cloned SIV bearing escape mutations in three immunodominant CTL epitopes, and followed viral evolution after infection. Here we show that each mutant epitope sequence continued to evolve in vivo, often re-establishing the original, CTL-susceptible sequence. We conclude that escape from CTL responses may exact a cost to viral fitness. In the absence of selective pressure upon transmission to new hosts, these original escape mutations can be lost. This suggests that some HIV CTL epitopes will be maintained in human populations.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Burton, D.R. Antibodies, viruses and vaccines. Nat. Rev. Immunol. 2, 706–713 (2002).
Ho, D.D. & Huang, Y. The HIV-1 vaccine race. Cell 110, 135–138 (2002).
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).
Wei, X. et al. Antibody neutralization and escape by HIV-1. Nature 422, 307–312 (2003).
McMichael, A.J. & Rowland-Jones, S.L. Cellular immune responses to HIV. Nature 410, 980–987 (2001).
Walker, B.D. & Korber, B.T. Immune control of HIV: the obstacles of HLA and viral diversity. Nat. Immunol. 2, 473–475 (2001).
McMichael, A.J. & Hanke, T. HIV vaccines 1983-2003. Nat. Med. 9, 874–880 (2003).
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).
Jin, X. et al. Dramatic rise in plasma viremia after CD8+ T cell depletion in simian immunodeficiency virus-infected macaques. J. Exp. Med. 189, 991–998 (1999).
Matano, T. et al. 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 (1998).
Schmitz, J.E. et al. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 283, 857–860 (1999).
Phillips, R.E. et al. Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition. Nature 354, 453–459 (1991).
Koenig, S. et al. Transfer of HIV-1-specific cytotoxic T lymphocytes to an AIDS patient leads to selection for mutant HIV variants and subsequent disease progression. Nat. Med. 1, 330–336 (1995).
Wolinsky, S.M. et al. Adaptive evolution of human immunodeficiency virus-type 1 during the natural course of infection. Science 272, 537–542 (1996).
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. Nat. Med. 3, 205–211 (1997).
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).
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).
Evans, D.T. et al. Virus-specific cytotoxic T-lymphocyte responses select for amino-acid variation in simian immunodeficiency virus env and Nef. Nat. Med. 5, 1270–1276 (1999).
Allen, T.M. et al. Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia. Nature 407, 386–390 (2000).
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).
McMichael, A. T cell responses and viral escape. Cell 93, 673–676 (1998).
O'Connor, D.H. et al. Acute phase cytotoxic T lymphocyte escape is a hallmark of simian immunodeficiency virus infection. Nat. Med. 8, 493–499 (2002).
Moore, C.B. et al. Evidence of HIV-1 adaptation to HLA-restricted immune responses at a population level. Science 296, 1439–1443 (2002).
Barouch, D.H. et al. Eventual AIDS vaccine failure in a rhesus monkey by viral escape from cytotoxic T lymphocytes. Nature 415, 335–339 (2002).
Goulder, P.J. et al. Evolution and transmission of stable CTL escape mutations in HIV infection. Nature 412, 334–338 (2001).
Regier, D.A. & Desrosiers, R.C. The complete nucleotide sequence of a pathogenic molecular clone of simian immunodeficiency virus. AIDS Res. Hum. Retroviruses 6, 1221–1231 (1990).
O'Connor, D.H. et al. 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 (2003).
Mothe, B.R. et al. Dominance of CD8 responses specific for epitopes bound by a single major histocompatibility complex class I molecule during the acute phase of viral infection. J. Virol. 76, 875–884 (2002).
Friedrich, T.C. et al. Extra-epitopic compensatory substitutions restore fitness to simian immunodeficiency virus variants that escape from an immunodominant cytotoxic T-lymphocyte response. J. Virol. (in the press).
Peyerl, F.W. et al. Simian-human immunodeficiency virus escape from cytotoxic T-lymphocyte recognition at a structurally constrained epitope. J. Virol. 77, 12572–12578 (2003).
Vogel, T.U. et al. Escape in one of two cytotoxic T-lymphocyte epitopes bound by a high-frequency major histocompatibility complex class I molecule, Mamu-A*02: a paradigm for virus evolution and persistence? J. Virol. 76, 11623–11636 (2002).
Rue, S.M., Roos, J.W., Amzel, L.M., Clements, J.E. & Barber, S.A. Hydrogen bonding at a conserved threonine in lentivirus capsid is required for virus replication. J. Virol. 77, 8009–8018 (2003).
von Schwedler, U.K., Stray, K.M., Garrus, J.E. & Sundquist, W.I. Functional surfaces of the human immunodeficiency virus type 1 capsid protein. J. Virol. 77, 5439–5450 (2003).
Knapp, L.A., Lehmann, E., Hennes, L., Eberle, M.E. & Watkins, D.I. High-resolution HLA-DRB typing using denaturing gradient gel electrophoresis and direct sequencing. Tissue Antigens 50, 170–177 (1997).
Hance, A.J. et al. Changes in human immunodeficiency virus type 1 populations after treatment interruption in patients failing antiretroviral therapy. J. Virol. 75, 6410–6417 (2001).
Sidney, J. et al. Definition of the Mamu A*01 peptide binding specificity: application to the identification of wild-type and optimized ligands from simian immunodeficiency virus regulatory proteins. J. Immunol. 165, 6387–6399 (2000).
Mothe, B.R. et al. Characterization of the peptide-binding specificity of Mamu-B*17 and identification of Mamu-B*17-restricted epitopes derived from simian immunodeficiency virus proteins. J. Immunol. 169, 210–219 (2002).
We gratefully acknowledge J. Helgeland, J. Mitchen, C. Bunger, K. Vielhuber and E. Rakasz; I. Bolton and the veterinarians and technicians of the WNPRC; and T. Jacoby and W. Rehrauer for their work in support of this study. We also thank W. Rehrauer for critical review of this manuscript. This work was supported by National Institutes of Health grants RO1-AI-46366, RO1-AI-49120 and RO1-AI-52056 to D.I.W., and P51 RR001676-43 to the WNPRC. D.I.W. is an Elizabeth Glaser Scientist. A.S. is supported by NIH-NIAID contract NO1-AI-95362.
The authors declare no competing financial interests.
About this article
Virus Research (2019)
Journal of Virology (2019)
Nature Reviews Immunology (2019)
PLOS Pathogens (2018)
Genotypic and Mechanistic Characterization of Subtype-Specific HIV Adaptation to Host Cellular Immunity
Journal of Virology (2018)