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:

Emerging cytopathic and antigenic simian immunodeficiency virus variants influence AIDS progression

Nature Medicine volume 5, pages 535–541 (1999)Cite this article

Abstract

Genetic variants of human and simian immunodeficiency virus (HIV and SIV) that evolve during the course of infection and progression to AIDS are phenotypically and antigenically distinct from their progenitor viruses present at early stages of infection. However, it has been unclear how these late variants, which are typically T-cell tropic, cytopathic and resistant to neutralizing antibodies, influence the development of clinical AIDS. To address this, we infected macaques with cloned SIVs representing prototype variants from early-, intermediate- and late-stage infection having biological characteristics typical of viruses found at similar stages of HIV infection in humans. These studies demonstrate that sequential, phenotypic and antigenic variants represent viruses that have become increasingly fit for replication in the host, and our data support the hypothesis that emerging variants have increased pathogenicity and drive disease progression in SIV and HIV infection.

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: Plasma viral RNA levels in SIVMne-infected macaques.
Figure 2: Viral RNA measurements from peripheral lymph node biopsies.
Figure 3: CD4+ T-lymphocyte levels in blood in SIVMne-infected macaques.

Similar content being viewed by others

References

  1. Åsjö, B. et al. Replicative capacity of human immunodeficiency virus from patients with varying severity of HIV infection. Lancet ii, 660–662 (1986).

    Google Scholar 

  2. Cheng-Mayer, C., Seto, D., Tateno, M. & Levy, J.A. Biologic features of HIV-1 that correlate with virulence in the host. Science 240, 80–82 (1988).

    Article  CAS  Google Scholar 

  3. Connor, R.I., Mohri, H., Cao, Y. & Ho, D.D. Increased viral burden and cytopathicity correlate temporally with CD4+ T-lymphocyte decline and clinical progression in human immunodeficiency virus type 1-infected individuals. J. Virol. 67, 1772–1777 (1993).

    CAS  PubMed  Google Scholar 

  4. Connor, R.I. & Ho, D.D. Human immunodeficiency virus type 1 variants with increased replicative capacity develop during the asymptomatic stage before disease progression. J. Virol. 68, 4400–4408 (1994).

    CAS  PubMed  Google Scholar 

  5. Fenyö, E.M., et al. Distinct replicative and cytopathic characteristics of human immunodeficiency virus isolates. J. Virol. 62, 4414–4419 (1988).

    PubMed  Google Scholar 

  6. Fenyö, E.M., Albert, J. & Åsjö, B. Replicative capacity, cytopathic effects and cell tropism of HIV. AIDS 3 (suppl), S5– S12 (1989).

    Article  Google Scholar 

  7. Schuitemaker, H. et al. Biological phenotype of human immunodeficiency virus type 1 clones at different stages of infection: progression of disease is associated with a shift from monocytotropic to T-cell-tropic virus populations. J. Virol. 66, 1354–1360 (1992).

    CAS  PubMed  Google Scholar 

  8. Tersmette, M. et al. Association between biological properties of human immunodeficiency virus variants and risk for AIDS and AIDS mortality. Lancet I, 983–985 (1989).

    Article  Google Scholar 

  9. Tersmette, M. et al. Evidence for a role of virulent human immunodeficiency virus (HIV) variants in the pathogenesis of acquired immunodeficiency syndrome: studies on sequential HIV isolates. J. Virol. 63, 2118–2125 (1989).

    CAS  PubMed  Google Scholar 

  10. Fiore, J.R. et al. The biological phenotype of HIV-1 is usually retained during and after sexual transmission. Virology 204, 297–303 (1994).

    Article  CAS  Google Scholar 

  11. Nielsen, C., Pedersen, C., Lundgren, J.D. & Gerstoft, J. Biological properties of HIV isolates in primary HIV infection: consequences for the subsequent course of infection. AIDS 7, 1035–1040 (1993).

    Article  CAS  Google Scholar 

  12. Glushakova, S. et al. Evidence for the HIV-1 phenotype switch as a causal factor in acquired immunodeficiency. Nature Med. 4, 346–349 (1998).

    Article  CAS  Google Scholar 

  13. Zack, J.A. & Overbaugh, J. SIV and HIV pathogenesis in animal systems. AIDS 8 (suppl 1), S43– S52 (1994).

    Google Scholar 

  14. Levy, J.A. Pathogenesis of human immunodeficiency virus infection. Microbiol. Rev. 57, 183–289 ( 1993).

    CAS  PubMed  Google Scholar 

  15. Fultz, P.N., McClure, H.M., Anderson, D.C. & Switzer, W.M. Identification and biological characterization of an acutely lethal variant of simian immunodeficiency virus from sooty mangabeys (SIV/SMM). AIDS Res. Hum. Retroviruses 5, 397– 409 (1989).

    Article  CAS  Google Scholar 

  16. Reimann, K.A. et al. A chimeric simian/human immunodeficiency virus expressing a primary patient human immunodeficiency virus type 1 isolate env causes an AIDS-like disease after in vivo passage in rhesus macaques. J. Virol. 70, 6922–6928 ( 1996).

    CAS  PubMed  Google Scholar 

  17. Joag, S.V. et al. Chimeric simian/human immunodeficiency virus that causes progressive loss of CD4+ T cells and AIDS in Pig-tailed macaques. J. Virol. 70, 3189–3197 ( 1996).

    CAS  PubMed  Google Scholar 

  18. Edmonson, P. et al. Evolution of a simian immunodeficiency virus pathogen. J. Virol. 72, 405–414 ( 1998).

    CAS  PubMed  Google Scholar 

  19. Kimata, J.T. & Overbaugh, J. The cytopathicity of a simian immunodeficiency virus Mne variant is determined by mutations in Gag and Env. J. Virol. 71, 7629–7639 (1997).

    CAS  PubMed  Google Scholar 

  20. Morton, W.R. et al. Transmission of the simian immunodeficiency virus SIVmne in macaques and baboons. J. Med. Primatol. 18, 237–245 (1989).

    Article  CAS  Google Scholar 

  21. Overbaugh, J., Rudensey, L.M., Papenhausen, M.D., Benveniste, R.E. & Morton, W.R. Variation in simian immunodeficiency virus env is confined to V1 and V4 during progression to simian AIDS. J. Virol. 65, 7025– 7031 (1991).

    CAS  PubMed  Google Scholar 

  22. Rudensey, L.M., Kimata, J.T., Benveniste, R.E. & Overbaugh, J. Progression to AIDS in macaques is associated with changes in the replication, tropism, and cytopathic properties of the simian immunodeficiency virus variant population. Virology 207, 528– 542 (1995).

    Article  CAS  Google Scholar 

  23. Rudensey, L.M., Kimata, J.T., Long, E.M., Chackerian, B. & Overbaugh, J. Changes in the extracellular envelope glycoprotein of variants that evolve during the course of simian immunodeficiency virus SIVMne infection affect neutralizing antibody recognition, syncytium formation, and macrophage tropism but not replication, cytopathicity, or CCR-5 coreceptor recognition. J. Virol. 72, 209– 217 (1998).

    CAS  PubMed  Google Scholar 

  24. Chackerian, B., Rudensey, L.M. & Overbaugh, J. Specific N-linked and O-linked glycosylation modifications in the envelope V1 domain of simian immunodeficiency virus variants that evolve in the host alter recognition by neutralizing antibodies. J. Virol. 71, 7719–27 ( 1997).

    CAS  PubMed  Google Scholar 

  25. Overbaugh, J. & Rudensey, L.M. Alterations in potential sites for glycosylation predominate during evolution of the simian immunodeficiency virus envelope gene in macaques. J. Virol. 66, 5937–5948 (1992).

    CAS  PubMed  Google Scholar 

  26. Kimata, J.T., Mozaffarian, A. & Overbaugh, J. A lymph node-derived cytopathic simian immunodeficiency virus Mne variant replicates in nonstimulated peripheral blood mononuclear cells. J. Virol. 72, 245– 256 (1998).

    CAS  PubMed  Google Scholar 

  27. Hirsch, V.M. et al. Patterns of viral replication correlate with outcome in simian immunodeficiency virus (SIV)-infected macaques: effects of prior immunization with a trivalent SIV vaccine in modified vaccinia virus Ankara. J. Virol. 70, 3741–3752 (1996).

    CAS  PubMed  Google Scholar 

  28. 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  Google Scholar 

  29. 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  Google Scholar 

  30. O'Brien, W.A. et al. Changes in plasma HIV-1 RNA and CD4+ lymphocyte counts and the risk of progression to AIDS. N. Engl. J. Med. 334 , 426–431 (1996).

    Article  CAS  Google Scholar 

  31. O'Brien, T.R. et al. Serum HIV-1 RNA levels and time to development of AIDS in the multicenter hemophilia cohort study. J. Am. Med. Assoc. 276, 105–110 (1996).

    Article  CAS  Google Scholar 

  32. Watson, A. et al. Plasma viremia in macaques infected with simian immunodeficiency virus: plasma viral load early in infection predicts survival. J. Virol. 71, 284–290 ( 1997).

    CAS  PubMed  Google Scholar 

  33. Mellors, J.W. et al. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann. Intern. Med. 126, 946–954 (1997).

    Article  CAS  Google Scholar 

  34. Connor, R.I. & Ho, D.D. Transmission and pathogenesis of human immunodeficiency virus type 1. AIDS Res. Hum. Retroviruses 10, 321–323 (1994).

    Article  CAS  Google Scholar 

  35. Miedema, F. et al. Changing virus-host interactions in the course of HIV-1 infection. Imm. Rev. 140, 35–72 (1994).

    Article  CAS  Google Scholar 

  36. Banapour, B., Marthas, M.L., Munn, R.J. & Luciw, P.A. In vitro macrophage tropism of pathogenic and nonpathogenic molecular clones of simian immunodeficiency virus (SIVMAC). Virology 183, 12–19 ( 1991).

    Article  CAS  Google Scholar 

  37. Kestler, H. et al. Induction of AIDS in rhesus monkeys by molecularly cloned simian immunodeficiency virus. Science 248, 1109–1112 (1990).

    Article  CAS  Google Scholar 

  38. Desrosiers, R.C. et al. Macrophage-tropic variants of SIV are associated with specific AIDS-related lesions but are not essential for the development of AIDS. Am. J. Pathol. 139, 29–35 (1991).

    CAS  PubMed  Google Scholar 

  39. Kimata, J.T. et al. Coreceptor specificity of temporal variants of SIVMne. J. Virol. (in the press).

  40. Chackerian, B., Long, E.M., Luciw, P.A. & Overbaugh, J. Human immunodeficiency virus type 1 coreceptors participate in postentry stages in the virus replication cycle and function in simian immunodeficiency virus infection. J. Virol. 71, 3932–3939 (1997).

    CAS  PubMed  Google Scholar 

  41. Reitter, J.N., Means, R.E. & Desrosiers, R.C. A role for carbohydrates in immune evasion in AIDS. Nature Med. 4, 679–684 (1998).

    Article  CAS  Google Scholar 

  42. Dailey, P.J., Zamround, M., Kelso, R., Kolberg, J. & Urdea, M. Quantitation of simian immunodeficiency virus (SIV) RNA in plasma of acute and chronically infected macaques using a branched DNA (bDNA) signal amplification assay. J. Med. Primatol. 24, 209 (1995).

    Google Scholar 

  43. Connor, R.I. et al. Temporal analyses of virus replication, immune responses, and efficacy in rhesus macaques immunized with a live, attenuated simian immunodeficiency virus vaccine. J. Virol. 72, 7501– 7509 (1998).

    CAS  PubMed  Google Scholar 

  44. Harris, M. et al. Correlation of viral load in plasma and lymph node tissue in HIV infection. J. Infect. Dis. 176, 1388 –1392 (1997).

    Article  CAS  Google Scholar 

  45. Marx, P.A. et al. Progesterone implants enhance SIV vaginal transmission and early virus load. Nature Med 2, 1084– 1089 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We acknowledge L. Rudensey, who did many of the early studies in the SIVMne system, including the construction and characterization of the intermediate virus; J. Booth and C. Wingfield for technical assistance with the bDNA assays; and E. Coon and E. Finn for assistance with processing of blood and virus co-cultures. We also thank B. Richardson for help with statistical analysis. This work was supported by NIH grants RO1 AI34251 and RR00166. J.T.K. was supported, in part, by NRSA postdoctoral fellowship F32 AI09337.

Author information

Author notes

  1. Julie Overbaugh

    Present address: Program in Molecular Medicine, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, C3-168, Seattle, Washington, 98109, USA

Authors and Affiliations

  1. Department of Microbiology, University of Washington, Seattle, 98195, Washington, USA

    Jason T. Kimata & Julie Overbaugh

  2. Washington Regional Primate Research Center, University of Washington, Seattle, 98195, Washington, USA

    LaRene Kuller & David B. Anderson

  3. Chiron Diagnostics, Chiron Reference Testing Laboratory , 61221 Hollis St., Emeryville, 94608, California , USA

    Peter Dailey

Authors
  1. Jason T. Kimata
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. LaRene Kuller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David B. Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peter Dailey
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Julie Overbaugh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Julie Overbaugh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kimata, J., Kuller, L., Anderson, D. et al. Emerging cytopathic and antigenic simian immunodeficiency virus variants influence AIDS progression. Nat Med 5, 535–541 (1999). https://doi.org/10.1038/8414

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/8414

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