Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Acute phase cytotoxic T lymphocyte escape is a hallmark of simian immunodeficiency virus infection

Nature Medicine volume 8, pages 493–499 (2002)Cite this article

Abstract

Cytotoxic T-lymphocyte (CTL) responses peak coincident with the decline in acute HIV viremia. Despite two reports of CTL-resistant HIV variants emerging during acute infection, the contribution of acute CTL escape to HIV pathogenesis remains unclear. Difficulties inherent in studying acute HIV infection can be overcome by modeling virus-host interactions in SIV-infected rhesus macaques. We sequenced 21 complete simian immunodeficiency virus (SIV)mac239 genomes at four weeks post-infection to determine the extent of acute CTL escape. Here we show that viruses from 19 of 21 macaques escaped from CTLs during acute infection and that these escape-selecting CTLs were responsive to lower concentrations of peptide than other SIV-specific CTLs. Interestingly, CTLs that require low peptide concentrations for stimulation (high 'functional avidity') are particularly effective at controlling other viral infections. Our results suggest that acute viral escape from CTLs is a hallmark of SIV infection and that CTLs with high functional avidity can rapidly select for escape variants.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Viruses from 21 SIV-infected macaques were screened for mixed-base heterogeneity during acute infection.
Figure 2: Twenty-two unique sites of mixed-base heterogeneity identified at 4 wk p.i. with molecularly cloned SIVmac239.
Figure 3: Eight viral regions exhibited variation consistent with CTL escape by 4 wk p.i.
Figure 4: Epitope avidity influences the rate of viral escape.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Koup, R.A. & Ho, D.D. Shutting down HIV. Nature 370, 416 (1994).

  2. 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 

  3. Reimann, K.A. et al. Immunopathogenic events in acute infection of rhesus monkeys with simian immunodeficiency virus of macaques. J. Virol. 68, 2362–2370 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Schmitz, J.E. et al. Control of viremia in simian immunodeficiency virus infection by CD8(+) lymphocytes. Science 283, 857–860 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. McMichael, A.J. & Rowland-Jones, S.L. Cellular immune responses to HIV. Nature 410, 980–987 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Day, C.L. et al. Relative dominance of epitope-specific cytotoxic T-lymphocyte responses in human immunodeficiency virus type 1-infected persons with shared HLA alleles. J. Virol. 75, 6279–6291 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Rowland-Jones, S.L. et al. How important is the 'quality' of the cytotoxic T lymphocyte (CTL) response in protection against HIV infection? Immunol. Lett 79, 15–20 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Kaul, R. et al. CD8(+) lymphocytes respond to different HIV epitopes in seronegative and infected subjects. J. Clin Invest 107, 1303–1310 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kuroda, M.J. et al. Comparative analysis of cytotoxic T lymphocytes in lymph nodes and peripheral blood of simian immunodeficiency virus-infected rhesus monkeys. J. Virol. 73, 1573–1579 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 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).

    Article  CAS  PubMed  Google Scholar 

  14. Goulder, P.J. et al. Substantial differences in specificity of HIV-specific cytotoxic T cells in acute and chronic HIV infection. J. Exp Med. 193, 181–194 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kaul, R. et al. Late seroconversion in HIV-resistant Nairobi prostitutes despite pre-existing HIV-specific CD8+ responses. J. Clin Invest 107, 341–349 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kaul, R. et al. New insights into HIV-1 specific cytotoxic T-lymphocyte responses in exposed, persistently seronegative Kenyan sex workers. Immunol. Lett 79, 3–13 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Van Baalen, C.A. et al. Kinetics of antiviral activity by human immunodeficiency virus type 1-specific cytotoxic T lymphocytes (CTL) and rapid selection of CTL escape virus in vitro. J. Virol. 72, 6851–6857 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  19. 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 

  20. Wilson, C.C. et al. Frequent detection of escape from cytotoxic T-lymphocyte recognition in perinatal human immunodeficiency virus (HIV) type 1 transmission: the ariel project for the prevention of transmission of HIV from mother to infant. J. Virol. 73, 3975–3985 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Soudeyns, H. et al. Selective pressure exerted by immunodominant HIV-1-specific cytotoxic T lymphocyte responses during primary infection drives genetic variation restricted to the cognate epitope. Eur J. Immunol. 29, 3629–3635 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Evans, D.T. et al. Virus-specific cytotoxic T-lymphocyte responses select for amino-acid variation in simian immunodeficiency virus Env and Nef. Nature Med. 5, 1270–1276 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Chen, Z.W. et al. Simian immunodeficiency virus evades a dominant epitope-specific cytotoxic T lymphocyte response through a mutation resulting in the accelerated dissociation of viral peptide and MHC class I. J. Immunol. 164, 6474–6479 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. 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  CAS  PubMed  Google Scholar 

  25. 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  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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  PubMed  Google Scholar 

  27. Slifka, M.K. & Whitton, J.L. Functional avidity maturation of CD8(+) T cells without selection of higher affinity TCR. Nature Immunol. 2, 711–717 (2001).

    Article  CAS  Google Scholar 

  28. Derby, M., Alexander-Miller, M., Tse, R. & Berzofsky, J. High-avidity CTL exploit two complementary mechanisms to provide better protection against viral infection than low-avidity CTL. J. Immunol. 166, 1690–1697 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Alexander-Miller, M.A., Leggatt, G.R. & Berzofsky, J.A. Selective expansion of high- or low-avidity cytotoxic T lymphocytes and efficacy for adoptive immunotherapy. Proc. Natl. Acad. Sci. USA 93, 4102–4107 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Alexander, L., Denekamp, L., Czajak, S. & Desrosiers, R.C. Nucleotides in the Infectious, Pathogenic Simian Immunodeficiency Virus Clone SIVmac239. J. Virol. 75, 4019–4022 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Robinson, S. et al. A commonly recognized simian immunodeficiency virus nef epitope presented to cytotoxic T lymphocytes of indian-origin rhesus monkeys by the prevalent major histocompatibility complex class I allele mamu-a*02. J. Virol. 75, 10179–10186 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Derby, M.A., Alexander-Miller, M.A., Tse, R. & Berzofsky, J.A. High-avidity CTL exploit two complementary mechanisms to provide better protection against viral infection than low-avitity CTL. J. Immunol. 166, 1690–1697 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Gallimore, A., Dumrese, T., Hengartner, H., Zinkernagel, R.M. & Rammensee, H.G. Protective immunity does not correlate with the hierarchy of virus-specific cytotoxic T cell responses to naturally processed peptides. J. Exp. Med. 187, 1647–1657 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gray, P.M., Parks, G.D. & Alexander-Miller, M.A. A novel CD8-independent high-avidity cytotoxic T-lymphocyte response directed against an epitope in the phosphoprotein of the paramyxovirus simian virus 5. J. Virol. 75, 10065–10072 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Allen, T.M. et al. CD8+ lymphocytes from simian immunodeficiency virus-infected rhesus macaques recognize 14 different epitopes bound by the major histocompatibility complex class I molecule Mamu-A*01: Implications for vaccine design and testing. J. Virol. 75, 738–749 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Vidal, C. et al. Lack of evidence of a stable viral load set-point in early stage asymptomatic patients with chronic HIV-1 infection. AIDS 12, 1285–9 (1998).

    Article  CAS  PubMed  Google Scholar 

  37. Mellors, J.W. et al. Quantitation of HIV-1 RNA in plasma predicts outcome after seroconversion. Ann. Intern. Med. 122, 573–579 (1995).

    Article  CAS  PubMed  Google Scholar 

  38. Mellors, J.W. et al. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 272, 1167–1170 (1996).

    Article  CAS  PubMed  Google Scholar 

  39. Cooper, S. et al. Analysis of a successful immune response against hepatitis C virus. Immunity 10, 439–449 (1999).

    Article  CAS  PubMed  Google Scholar 

  40. Goulder, P.J. et al. Evolution and transmission of stable CTL escape mutations in HIV infection. Nature 412, 334–338 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. 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  PubMed  Google Scholar 

  42. Allen, T. et al. Tat vaccinated macaques do not control simian immunodeficiency virus SIVmac239 replication. J. Virol. 76, 4108–4112 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Allen, T.M. et al. Induction of AIDS virus-specific CTL activity in fresh, unstimulated peripheral blood lymphocytes from rhesus macaques vaccinated with a DNA prime/modified vaccinia virus Ankara boost regimen. . Immunol. 164, 4968–4978 (2000).

    Article  CAS  Google Scholar 

  44. Trivedi, P. et al. Intrarectal transmission of simian immunodeficiency virus in rhesus macaques: selective amplification and host responses to transient or persistent viremia. J. Virol. 70, 6876–6883 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 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  PubMed  Google Scholar 

  46. 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 simian immunodeficiency virus. J. Immunol. 160, 6062–6071 (1998).

    CAS  PubMed  Google Scholar 

  47. Allen, T.M. et al. CD8(+) lymphocytes from simian immunodeficiency virus-infected rhesus macaques recognize 14 different epitopes bound by the major histocompatibility complex class I molecule mamu-A*01: Implications for vaccine design and testing. J. Virol. 75, 738–749 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 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 

  49. Nei, M. & Jin, L. Variances of the average numbers of nucleotide substitutions within and between populations. Mol. Biol. Evol. 6, 290–300 (1989).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by NIH grants AI49120, AI 46366, RR15371 and RR0167. D.I.W. is an Elizabeth Glaser Scientist.

Author information

Author notes

  1. David H. O'Connor, Todd M. Allen and Thorsten U. Vogel: D.H.O., T.M.A. and T.U.V contributed equally to this study.

Authors and Affiliations

  1. Wisconsin Regional Primate Research Center and Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin, USA

    David H. O'Connor, Todd M. Allen, Thorsten U. Vogel, Peicheng Jing, Ivna P. DeSouza, Elizabeth Dodds, Edward J. Dunphy, Cheri Melsaether, Bianca Mothé, Hiroshi Yamamoto, Helen Horton, Nancy Wilson & David I. Watkins

  2. Department of Biological Sciences, University of South Carolina, Columbia, South Carolina, USA

    Austin L. Hughes

Authors
  1. David H. O'Connor
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Todd M. Allen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thorsten U. Vogel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peicheng Jing
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ivna P. DeSouza
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elizabeth Dodds
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Edward J. Dunphy
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Cheri Melsaether
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Bianca Mothé
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hiroshi Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Helen Horton
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Nancy Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Austin L. Hughes
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. David I. Watkins
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David I. Watkins.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

O'Connor, D., Allen, T., Vogel, T. et al. Acute phase cytotoxic T lymphocyte escape is a hallmark of simian immunodeficiency virus infection. Nat Med 8, 493–499 (2002). https://doi.org/10.1038/nm0502-493

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0502-493

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing