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:

Viremia control following antiretroviral treatment and therapeutic immunization during primary SIV251 infection of macaques

Nature Medicine volume 6, pages 1140–1146 (2000)Cite this article

Abstract

Prolonged antiretroviral therapy (ART) is not likely to eradicate human immunodeficiency virus type I (HIV-I) infection. Here we explore the effect of therapeutic immunization in the context of ART during primary infection using the simian immunodeficiency virus (SIV251) macaque model. Vaccination of rhesus macaques with the highly attenuated poxvirus-based NYVAC-SIV vaccine expressing structural genes elicited vigorous virus-specific CD4+ and CD8+ T cell responses in macaques that responded effectively to ART. Following discontinuation of a six-month ART regimen, viral rebound occurred in most animals, but was transient in six of eight vaccinated animals. Viral rebound was also transient in four of seven mock-vaccinated control animals. These data establish the importance of antiretroviral treatment during primary infection and demonstrate that virus-specific immune responses in the infected host can be expanded by therapeutic immunization.

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: Statistical analysis of the plasma virus load and proliferative response to p27 Gag and gp120 in the immunized ART-treated macaques from groups A(▪), B(●) and C(○).
Figure 2: Inverse correlation between LPR and viremia.
Figure 3: Induction of CD8+ t cell response by NYVAC-SIV-gpe immunization.
Figure 4: Viral load, p27 Gag and gp120 LPR in all animal groups before and during immunization and ART and after ART suspension.
Figure 5: Mamu-A*01-Gag 181-tetramer staining in ex vivo PBMC of macaques following ART discontinuation.

Similar content being viewed by others

References

  1. Palella, F.J. Jr. et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N. Engl. J. Med. 338, 853–860 (1998).

    Article  PubMed  Google Scholar 

  2. Finzi, D. et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 278, 1295–1300 (1997).

    Article  CAS  PubMed  Google Scholar 

  3. Wong, J.K. et al. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 278, 1291– 1295 (1997).

    Article  CAS  PubMed  Google Scholar 

  4. Davey, R.T. Jr. et al. HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proc. Natl Acad. Sci. USA 96, 15109–15114 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lisziewicz, J. et al. Control of HIV despite the discontinuation of antiretroviral therapy. N. Engl. J. Med. 340, 1683– 1684 (1999).

    Article  CAS  PubMed  Google Scholar 

  6. Ortiz, G.M. et al. HIV-1-specific immune responses in subjects who temporarily contain virus replication after discontinuation of highly active antiretroviral therapy. J. Clin. Invest. 104, R13– R18 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Borrow, P., Lewicki, H., Hahn, B.H., Shaw, G.M. & Oldstone, M.B. A. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 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 

  9. Nixon, D.F. et al. HIV-1 Gag-specific cytotoxic T lymphocytes defined with recombinant vaccinia virus and synthetic peptides. Nature 336, 484–487 (1988).

    Article  CAS  PubMed  Google Scholar 

  10. Pantaleo, G. et al. Major expansion of CD8+ T cells with a predominant V beta usage during the primary immune response to HIV. Nature 370, 463–467 (1994).

    Article  CAS  PubMed  Google Scholar 

  11. Rinaldo, C. et al. High levels of anti-human immunodeficiency virus type 1 (HIV-1) memory cytotoxic T-lymphocyte activity and low viral load are associated with lack of disease in HIV-1-infected long-term nonprogressors. J. Virol. 69, 5838–5842 ( 1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Autran, B. et al. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 277, 112–116 ( 1997).

    Article  CAS  PubMed  Google Scholar 

  13. Oxenius, A. et al. Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of CD8+ and CD4+ T lymphocytes. Proc. Natl Acad. Sci. USA 97, 3382– 3387 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Rosenberg, E.S. et al. Vigorous HIV-1-specific CD4+ t cell responses associated with control of viremia. Science 278, 1447– 1450 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Gray, C.M. et al. Frequency of class I HLA-restricted anti-HIV CD8+ T cells in individuals receiving highly active antiretroviral therapy (HAART). J. Immunol. 162, 1780–1788 (1999).

    CAS  PubMed  Google Scholar 

  16. Morris, L. et al. HIV-1 antigen-specific and -nonspecific B cell responses are sensitive to combination antiretroviral therapy. J. Exp. Med. 188, 233–245 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ogg, G.S. et al. Decay kinetics of human immunodeficiency virus-specific effector cytotoxic T lymphocytes after combination antiretroviral therapy. J. Virol. 73, 797–800 ( 1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Benson, J. et al. Recombinant vaccine-induced protection against the highly pathogenic SIV mac251: dependence on route of challenge exposure . J. Virol. 72, 4170–4182 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Evans, T.G. et al. A canarypox vaccine expressing multiple human immunodeficiency virus type 1 genes given alone or with rgp120 elicits broad and durable CD8+ cytotoxic T lymphocyte responses in seronegative volunteers. J. Infect. Dis. 180, 290–298 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Hanke, T. et al. Effective induction of simian immunodeficiency virus-specific cytotoxic T lymphocytes in macaques by using a multiepitope gene and DNA prime-modified vaccinia virus ankara boost vaccination regimen. J. Virol. 73, 7524–7532 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Seth, A. et al. Immunization with a modified vaccinia virus expressing simian immunodeficiency virus (SIV) Gag-Pol primes for an anamnestic Gag-specific cytotoxic T-lymphocyte response and is associated with reduction of viremia after SIV challenge. J. Virol. 74, 2502– 2509 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Franchini, G. et al. Highly attenuated HIV type 2 recombinant poxviruses, but not HIV-2 recombinant Salmonella vaccines, induce long-lasting protection in rhesus macaques. AIDS Res. Hum. Retroviruses 11, 909–920 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. Klein, J. et al. Nomenclature for the major histocompatibility complexes of different species: a proposal. Immunogenetics 31, 217–219 (1990).

    CAS  PubMed  Google Scholar 

  24. 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 PCR-SSP and direct sequencing. Tissue Antigens 50, 657–661 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. 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 

  26. Miller, M.D., Yamamoto, H., Hughes, A.L., Watkins, D.I. & Letvin, N.L. Definition of an epitope and MHC class I molecule recognized by gag-specific cytotoxic T lymphocytes in SIVmac-infected rhesus monkeys. J. Immunol. 147, 320–329 (1991).

    CAS  PubMed  Google Scholar 

  27. Franchini, G. et al. Sequence of simian immunodeficiency virus and its relationship to the human immunodeficiency viruses. Nature 328, 539–543 (1987).

    Article  CAS  PubMed  Google Scholar 

  28. Letvin, N.L. et al. The CD8+ T lymphocyte response during primary SIVmac infection . Adv. Exp. Med. Biol. 452, 177– 179 (1998).

    Article  CAS  PubMed  Google Scholar 

  29. Binley, J.M. et al. The relationship between T cell proliferative responses and plasma viremia during treatment of human immunodeficiency virus type 1 infection with combination antiretroviral therapy. J. Infect. Dis. 181, 1249–1263 (2000).

    Article  CAS  PubMed  Google Scholar 

  30. Haslett, P.A. et al. Strong human immunodeficiency virus (HIV)-specific CD4+ T cell responses in a cohort of chronically infected patients are associated with interruptions in anti-HIV chemotherapy. J. Infect. Dis. 181, 1264–1272 (2000).

    Article  CAS  PubMed  Google Scholar 

  31. Herbein, G. et al. Apoptosis of CD8+ T cells is mediated by macrophages through interaction of HIV gp120 with chemokine receptor CXCR4. Nature 395, 189–194 ( 1998).

    Article  CAS  PubMed  Google Scholar 

  32. Li, C.J., Friedman, D.J., Wang, C., Metelev, V. & Pardee, A.B. Induction of apoptosis in uninfected lymphocytes by HIV-1. Science 268, 429– 431 (1995).

    Article  CAS  PubMed  Google Scholar 

  33. Westendorp, M.O. et al. Sensitization of T cells to CD95-mediated apoptosis by HIV-1 . Nature 375, 497–500 (1995).

    Article  CAS  PubMed  Google Scholar 

  34. Pitcher, C.J. et al. HIV-1-specific CD4+ T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression . Nature Med. 5, 518–525 (1999).

    Article  CAS  PubMed  Google Scholar 

  35. Yasutomi, Y. et al. A vaccine-elicited, single viral epitope-specific cytotoxic T lymphocyte response does not protect against intravenous, cell-free simian immunodeficiency virus challenge. J. Virol. 69, 2279–2284 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Allen, T.M. et al. Acute viral escape from cytotoxic T lymphocytes: implications for HIV vaccine design. Nature (in press).

  37. Tsai, C.-C. et al. Prevention of simian immunodeficiency virus infection in macaques by 9-(2-phosphonylmethoxypropyl) adenine (PMPA). Science 270, 1197–1199 (1995).

    Article  CAS  PubMed  Google Scholar 

  38. Tartaglia, J. et al. NYVAC: a highly attenuated strain of vaccinia virus. Virology 188, 217–232 ( 1992).

    Article  CAS  PubMed  Google Scholar 

  39. Barouch, D.H. et al. Augmentation of immune responses to HIV-1 and simian immunodeficiency virus DNA vaccines by IL-2/Ig plasmid administration in rhesus monkeys. Proc. Natl Acad. Sci. USA 97, 4192– 4197 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Jacobson, E.L., Pilaro, F. & Smith, K.A. Rational interleukin 2 therapy for HIV positive individuals: daily low doses enhance immune function without toxicity . Proc. Natl Acad. Sci. USA 93, 10405– 10410 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kovacs, J.A. et al. Controlled trial of interleukin-2 infusions in patients infected with the human immunodeficiency virus. N. Engl. J. Med. 335, 1350–1356 (1996).

    Article  CAS  PubMed  Google Scholar 

  42. Romano, J.W., Williams, K.G., Shurtliff, R.N., Ginocchio, C. & Kaplan, M. NASBA technology: isothermal RNA amplification in qualitative and quantitative diagnostics. Immunol. Invest. 26, 15–28 (1997).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank R. Klausner, M. Klein, R. Yarchoan and R. Little for discussion; R. Pal for the SIV251 stock; C. Mclaren for Stavudine; X. Wang for making the tetramers; the ABL staff for animal care; and S. Snodgrass for editorial assistance. M.Poudyal. was supported by the National Foundation for Biomedical Research as a Clinical Research Training Program Scholar.

Author information

Authors and Affiliations

  1. National Cancer Institute, Basic Research Laboratory , 41/D804, Bethesda, 20892, Maryland, USA

    Zdenek Hel, Monita Poudyal, Wen-Po Tsai, Laura Giuliani & Genoveffa Franchini

  2. National Cancer Institute, Biostatistics and Data Management Section, Bethesda, 20892, Maryland, USA

    David Venzon

  3. Advanced BioScience Laboratories, Inc., Kensington, 20895, Maryland, USA

    Ruth Woodward & Phillip Markham

  4. National Cancer Institute, Experimental Immunology Branch, 10/4B17, Bethesda, 20892, Maryland , USA

    Claire Chougnet & Gene Shearer

  5. Emory University Vaccine Center at Yerkes, Atlanta, 30329, Georgia, USA

    John D. Altman

  6. Wisconsin Regional Primate Research Center, Madison, 53715, Wisconsin, USA

    David Watkins

  7. Gilead Sciences, Foster City, 94404, California, USA

    Norbert Bischofberger

  8. Institute of Human Virology, 725 West Lombard Street, Baltimore, 21201, MD

    Alashle Abimiku

  9. Aventis Pasteur, Ltd., Toronto, M2R 3T4, Ontario, Canada

    James Tartaglia

  10. Virogenetics Corporation, Troy, 12180, New York, USA

    James Tartaglia

Authors
  1. Zdenek Hel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David Venzon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Monita Poudyal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wen-Po Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Laura Giuliani
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ruth Woodward
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Claire Chougnet
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gene Shearer
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. John D. Altman
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. David Watkins
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Norbert Bischofberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Alashle Abimiku
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Phillip Markham
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. James Tartaglia
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Genoveffa Franchini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Genoveffa Franchini.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hel, Z., Venzon, D., Poudyal, M. et al. Viremia control following antiretroviral treatment and therapeutic immunization during primary SIV251 infection of macaques. Nat Med 6, 1140–1146 (2000). https://doi.org/10.1038/80481

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/80481

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