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Virus-specific cytotoxic T-lymphocyte responses select for amino-acid variation in simian immunodeficiency virus Env and Nef

Nature Medicine volume 5, pages 1270–1276 (1999)Cite this article

Abstract

Cytotoxic T-lymphocyte (CTL) responses to human immunodeficiency virus arise early after infection, but ultimately fail to prevent progression to AIDS. Human immunodeficiency virus may evade the CTL response by accumulating amino-acid replacements within CTL epitopes. We studied 10 CTL epitopes during the course of simian immunodeficiency virus disease progression in three related macaques. All 10 of these CTL epitopes accumulated amino-acid replacements and showed evidence of positive selection by the time the macaques died. Many of the amino-acid replacements in these epitopes reduced or eliminated major histocompatibility complex class I binding and/or CTL recognition. These findings strongly support the CTL 'escape' hypothesis.

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Figure 1: Pedigree of an MHC-defined family of rhesus macaques.
Figure 2: Evolution of the plasma virus population in Nef from macaque D.
Figure 3: Evolution of the plasma virus population in Env from macaque D.
Figure 4: Analysis of sequences isolated from MHC-defined rhesus macaques at time of death.
Figure 5: Recognition of epitope variants by CTLs from macaques C, A and D.

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Acknowledgements

We thank L. Smith for help in preparing this manuscript and B. Becker for help with illustration. We thank J. Scheffler for initially identifying this family, and J. Mitchen, M. Dykhuizen and L. Acker for infecting the macaques, collecting blood and monitoring disease progression. We also thank J. Malter, S. Wolinsky and G. Watkins for critical review. This work was supported by grants from the National Institutes of Health (AI32426, AI42641, and AI41913 to D.I.W.; AI36643 to C.D.P.; AI15486 to R.D.; GM34940 to A.L.H.; AI38081 to Epimmune; and RR00167 to the Wisconsin Regional Primate Research Center). D.I.W. is an Elizabeth Glaser Scientist.

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Author notes

  1. David T. Evans

    Present address: New England Regional Primate Research Center, Harvard Medical School, One Pine Hill Drive, Southborough, Massachusetts, 01772, USA

  2. John L. Dzuris

    Present address: Department of Biology, East Carolina University, Greenville, North Carolina, 27858, USA

  3. David T. Evans and David H. O'Connor: D.T.E. and D.H.O. contributed equally to this study.

Authors and Affiliations

  1. Wisconsin Regional Primate Research Center, University of Wisconsin, 1220 Capitol Court, Madison, 53715, Wisconsin, USA

    David T. Evans, David H. O'Connor, Peicheng Jing, Todd M. Allen, Helen Horton, John E. Venham, Thorsten Vogel, C. David Pauza & David I. Watkins

  2. Epimmune, 5820 Nancy Ridge Drive, San Diego, 92121, California, USA

    John L. Dzuris, John Sidney & Alessandro Sette

  3. Institute of Molecular Evolutionary Genetics, The Pennsylvania State University, University Park, 16802, Pennsylvania, USA

    Jack da Silva & Austin L. Hughes

  4. Laboratory of Genetics, Genetics Building, University of Wisconsin, Madison, 53715, Wisconsin, USA

    Richard A. Rudersdorf & Robert DeMars

  5. Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, 53715, Wisconsin, USA

    C. David Pauza & David I. Watkins

  6. Biomedical Primate Research Centre-TNO, P. O. Box 5815, Rijswijk, 2280 HV, The Netherlands

    Ronald E. Bontrop

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Correspondence to David I. Watkins.

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Evans, D., O'Connor, D., Jing, P. 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). https://doi.org/10.1038/15224

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