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Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia

Nature volume 407, pages 386–390 (2000)Cite this article

Abstract

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections are characterized by early peaks of viraemia that decline as strong cellular immune responses develop1,2. Although it has been shown that virus-specific CD8-positive cytotoxic T lymphocytes (CTLs) exert selective pressure during HIV and SIV infection3,4,5,6,7,8,9,10,11, the data have been controversial12,13. Here we show that Tat-specific CD8-positive T-lymphocyte responses select for new viral escape variants during the acute phase of infection. We sequenced the entire virus immediately after the acute phase, and found that amino-acid replacements accumulated primarily in Tat CTL epitopes. This implies that Tat-specific CTLs may be significantly involved in controlling wild-type virus replication, and suggests that responses against viral proteins that are expressed early during the viral life cycle might be attractive targets for HIV vaccine development.

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Figure 1: Quantitation of CD8-positive T-lymphocyte responses to various Mamu-A*01-bound peptides.
Figure 2: Variation is present in the SL8 epitope of all 10 Mamu-A*01-positive animals after acute SIV infection using analysis of clones isolated from plasma virus.
Figure 3: CTL analyses of CD8-positive T-lymphocytes stimulated with the SL8 peptide.
Figure 4: Inverse correlation between plasma viral concentrations and peak dN in Tat.

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References

  1. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Yasutomi, Y., Reimann, K., Lord, C., Miller, M. & Letvin, N. Simian immunodeficiency virus-specific CD8+ lymphocyte response in acutely infected rhesus monkeys. J. Virol. 67, 1707–1711 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Goulder, P. J. R. et al. Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nature Med. 3, 212–217 (1997).

    Article  CAS  Google Scholar 

  4. Wolinsky, S. M. et al. Adaptive evolution of human immunodeficiency virus-type 1 during the natural course of infection. Science 272 , 537–542 (1996).

    Article  ADS  CAS  Google Scholar 

  5. 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. Nature Med. 1, 330– 336 (1995).

    Article  CAS  Google Scholar 

  6. Mortara, L. et al. Selection of virus variants and emergence of virus escape mutants after immunization with an epitope vaccine. J. Virol. 72, 1403–1410 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Evans, D. T. et al. Virus-specific CTL responses select for amino acid variation in SIV Env and Nef. Nature Med. 5, 1270– 1276 (1999).

    Article  CAS  Google Scholar 

  8. Phillips, R. E. et al. Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition. Nature 354, 453–459 (1991).

    Article  ADS  CAS  Google Scholar 

  9. Couillin, I. et al. Impaired cytotoxic T lymphocyte recognition due to genetic variations in the main immunogenic region of the human immunodeficiency virus 1 NEF protein. J. Exp. Med. 180, 1129– 1134 (1994).

    Article  CAS  Google Scholar 

  10. 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).

    Article  ADS  CAS  Google Scholar 

  11. 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. Nature Med. 3, 205– 211 (1997).

    Article  CAS  Google Scholar 

  12. Balter, M. Modest Briton stirs up storm with views on role of CTLs. Science 280, 1860–1861 ( 1998).

    Article  CAS  Google Scholar 

  13. Meyerhans, A. et al. In vivo persistence of a HIV-1-encoded HLA-B27-restricted cytotoxic T lymphocyte epitope despite specific in vitro reactivity. Eur. J. Immunol. 21, 2637– 2640 (1991).

    Article  CAS  Google Scholar 

  14. Allen, T. M. et al. CD8+ lymphocytes from SIV-infected rhesus macaques recognize 27 different peptides bound by a single MHC class I molecule: Implications for vaccine design and testing. J. Virol. (in the press).

  15. Allen, T. M. et al. Characterization of the peptide-binding motif of a rhesus MHC class I molecule (Mamu-A*01) that binds an immunodominant CTL epitope from SIV. J. Immunol. 160, 6062– 6071 (1998).

    CAS  PubMed  Google Scholar 

  16. Price, G. E., Ou, R., Jiang, H., Huang, L. & Moskophidis, D. Viral escape by selection of cytotoxic T cell-resistant variants in influenza A virus pneumonia. J. Exp. Med. 191, 1853–1867 (2000).

    Article  CAS  Google Scholar 

  17. Kimura, M. Preponderance of synonymous changes as evidence for the neutral theory of molecular evolution. Nature 267, 275– 276 (1977).

    Article  ADS  CAS  Google Scholar 

  18. Hughes, A. L. & Nei, M. Pattern of nucleotide substitution at major histocompatibility complex class I loci reveals overdominant selection. Nature 335, 167–170 (1988).

    Article  ADS  CAS  Google Scholar 

  19. Allen, T. M. et al. Induction of AIDS virus-specific CTL activity in fresh, unstimulated PBL from rhesus macaques vaccinated with a DNA prime/MVA boost regimen. J. Immunol. 164, 4968–4978 (2000).

    Article  CAS  Google Scholar 

  20. Coffin, J. M. HIV population dynamics in vivo: Implications for genetic variation, pathogenesis, and therapy. Science 267, 483–489 (1995).

    Article  ADS  CAS  Google Scholar 

  21. Collins, K. L., Chen, B. K., Kalams, S. A., Walker, B. D. & Baltimore, D. HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes. Nature 391, 397–401 ( 1998).

    Article  ADS  CAS  Google Scholar 

  22. Cafaro, A. et al. Control of SHIV-89.6P-infection of cynomolgus monkeys by HIV-1 Tat protein vaccine. Nature Med. 5, 643– 650 (1999).

    Article  CAS  Google Scholar 

  23. Pauza, C. D. et al. Vaccination with Tat toxoid attenuates disease in simian/HIV-challenged macaques. Proc. Natl Acad. Sci. USA 97, 3515–3519 (2000).

    Article  ADS  CAS  Google Scholar 

  24. Osterhaus, A. D. M. E. et al. Vaccination with Rev and Tat against AIDS. Vaccine 17, 2713–2714 ( 1999).

    Article  CAS  Google Scholar 

  25. Altman, J. D. et al. Phenotypic analysis of antigen-specific T lymphocytes. Science 274, 94–96 ( 1996).

    Article  ADS  CAS  Google Scholar 

  26. Knapp, L. A., Lehmann, E., Piekarczyk, M. S., Urvater, J. A. & Watkins, D. I. A high frequency of Mamu-A*01 in the rhesus macaque detected by polymerase chain reaction with sequence-specific primers and direct sequencing. Tissue Antigens 50, 657–661 (1997).

    Article  CAS  Google Scholar 

  27. 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).

    Article  CAS  Google Scholar 

  28. Nei, M. & Gojobori, T. Simple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions. Mol. Biol. Evol. 3, 418–426 (1986).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank L. Smith and B. Becker for preparation of this manuscript and C. D. Pauza and the Immunology and Virology Core Laboratory for infection with molecularly cloned SIVMAC239 nef stop and monitoring of macaques. This work was supported by the NIAID, NCRR and the The James B. Pendleton Charitable Trust. D.I.W. is an Elizabeth Glaser scientist.

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Author notes

  1. Todd M. Allen, David H. O'Connor and Ronald C. Desrosiers: These authors contributed equally to this work

Authors and Affiliations

  1. Wisconsin Regional Primate Research Center, University of Wisconsin, 1220 Capitol Court, Madison, 53715-1299, Wisconsin, USA

    Todd M. Allen, David H. O'Connor, Peicheng Jing, Bianca R. Mothé, Thorsten U. Vogel, Ed Dunphy, Max E. Liebl, Carol Emerson, Nancy Wilson & David I. Watkins

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

    John L. Dzuris & Alessandro Sette

  3. Northwestern University Medical School, 303 East Chicago, Room 3-735 Tarry Building, Chicago, 60611-3008, Illinois, USA

    Kevin J. Kunstman & Steven M. Wolinsky

  4. Emory Vaccine Center, Emory University School of Medicine, G211 Rollins Research Building, 1510 Clifton Road, Atlanta, 30322, Georgia, USA

    Xiaochi Wang & John D. Altman

  5. St. Luke’s/Roosevelt Hospital, Obesity Research Center, 1090 Amsterdam Avenue, Suite 14B, New York, 10025, New York, USA

    David B. Allison

  6. Department of Biological Sciences, 401 Coker Life Sciences, University of South Carolina, Columbia, 29208, South Carolina, USA

    Austin L. Hughes

  7. New England Regional Primate Research Center, One Pine Hill Drive, Southborough, 01772-9102, Massachusetts, USA

    Ronald C. Desrosiers

  8. Dept. of Pathology and Laboratory Medicine, University of Wisconsin, 1300 University Avenue, Madison, 53706-1532, Wisconsin, USA

    David I. Watkins

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  1. Todd M. Allen
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Correspondence to David I. Watkins.

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Allen, T., O'Connor, D., Jing, P. et al. Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia. Nature 407, 386–390 (2000). https://doi.org/10.1038/35030124

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