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.

CD4 downregulation by memory CD4+ T cells in vivo renders African green monkeys resistant to progressive SIVagm infection

Abstract

African green monkeys (genus Chlorocebus) can be infected with species-specific simian immunodeficiency virus (SIVagm) but do not develop AIDS. These natural hosts of SIV, like sooty mangabeys, maintain high levels of SIV replication but have evolved to avoid immunodeficiency. Elucidating the mechanisms that allow natural hosts to coexist with SIV without overt disease may provide crucial information for understanding AIDS pathogenesis. Here we show that many CD4+ T cells from African green monkeys downregulate CD4 in vivo as they enter the memory pool; that downregulation of CD4 by memory T cells is independent of SIV infection; that the CD4 memory T cells maintain functions that are normally attributed to CD4+ T cells, including production of interleukin-2 (IL-2), production of IL-17, expression of forkhead box P3 and expression of CD40 ligand; that loss of CD4 expression protects these T cells from infection by SIVagm in vivo; and that these CD4 T cells can maintain major histocompatibility complex class II restriction. These data show that the absence of SIV-induced disease progression in natural host species may be partially explained by preservation of a subset of T cells that maintain CD4+ T cell function while being resistant to SIV infection in vivo.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Phenotypic analysis of T cell populations in vervet African green monkeys.
Figure 2: CD8α and CD4 expression by naive and memory CD4+ T cells.
Figure 3: CD4CD8αdim T cells can develop from memory CD4+ T cells.
Figure 4: CD4CD8αdim T cells can preserve CD4+ T-cell function.
Figure 5: Infection frequencies of lymphocyte subsets.

References

  1. Hahn, B.H., Shaw, G.M., De Cock, K.M. & Sharp, P.M. AIDS as a zoonosis: scientific and public health implications. Science 287, 607–614 (2000).

    Article  CAS  Google Scholar 

  2. Ling, B., Veazey, R.S. & Marx, P.A. Nonpathogenic CCR2-tropic SIVrcm after serial passage and its effect on SIVmac infection of Indian rhesus macaques. Virology 379, 38–44 (2008).

    Article  CAS  Google Scholar 

  3. Zhang, Y. et al. Use of inhibitors to evaluate coreceptor usage by simian and simian/human immunodeficiency viruses and human immunodeficiency virus type 2 in primary cells. J. Virol. 74, 6893–6910 (2000).

    Article  CAS  Google Scholar 

  4. Beer, B.E. et al. Characterization of novel simian immunodeficiency viruses from red-capped mangabeys from Nigeria (SIVrcmNG409 and -NG411). J. Virol. 75, 12014–12027 (2001).

    Article  CAS  Google Scholar 

  5. Pandrea, I., Sodora, D.L., Silvestri, G. & Apetrei, C. Into the wild: simian immunodeficiency virus (SIV) infection in natural hosts. Trends Immunol. 29, 419–428 (2008).

    Article  CAS  Google Scholar 

  6. Silvestri, G., Paiardini, M., Pandrea, I., Lederman, M.M. & Sodora, D.L. Understanding the benign nature of SIV infection in natural hosts. J. Clin. Invest. 117, 3148–3154 (2007).

    Article  CAS  Google Scholar 

  7. Hirsch, V.M. What can natural infection of African monkeys with simian immunodeficiency virus tell us about the pathogenesis of AIDS? AIDS Rev. 6, 40–53 (2004).

    PubMed  Google Scholar 

  8. Goldstein, S. et al. Comparison of simian immunodeficiency virus SIVagmVer replication and CD4+ T cell dynamics in vervet and sabaeus African green monkeys. J. Virol. 80, 4868–4877 (2006).

    Article  CAS  Google Scholar 

  9. Pandrea, I. et al. Simian immunodeficiency virus SIVagm.sab infection of Caribbean African green monkeys: a new model for the study of SIV pathogenesis in natural hosts. J. Virol. 80, 4858–4867 (2006).

    Article  CAS  Google Scholar 

  10. Goldstein, S. et al. Wide range of viral load in healthy African green monkeys naturally infected with simian immunodeficiency virus. J. Virol. 74, 11744–11753 (2000).

    Article  CAS  Google Scholar 

  11. Silvestri, G. et al. Nonpathogenic SIV infection of sooty mangabeys is characterized by limited bystander immunopathology despite chronic high-level viremia. Immunity 18, 441–452 (2003).

    Article  CAS  Google Scholar 

  12. Pandrea, I. et al. Simian immunodeficiency viruses replication dynamics in African non-human primate hosts: common patterns and species-specific differences. J. Med. Primatol. 35, 194–201 (2006).

    Article  Google Scholar 

  13. Barry, A.P. et al. Depletion of CD8+ cells in sooty mangabey monkeys naturally infected with simian immunodeficiency virus reveals limited role for immune control of virus replication in a natural host species. J. Immunol. 178, 8002–8012 (2007).

    Article  CAS  Google Scholar 

  14. Dunham, R. et al. The AIDS resistance of naturally SIV-infected sooty mangabeys is independent of cellular immunity to the virus. Blood 108, 209–217 (2006).

    Article  CAS  Google Scholar 

  15. Klatt, N.R. et al. Availability of activated CD4+ T cells dictates the level of viremia in naturally SIV-infected sooty mangabeys. J. Clin. Invest. 118, 2039–2049 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Pandrea, I. et al. Paucity of CD4+ CCR5+ T cells may prevent transmission of simian immunodeficiency virus in natural nonhuman primate hosts by breast-feeding. J. Virol. 82, 5501–5509 (2008).

    Article  CAS  Google Scholar 

  17. Gordon, S.N. et al. Short-lived infected cells support virus replication in sooty mangabeys naturally infected with simian immunodeficiency virus: implications for AIDS pathogenesis. J. Virol. 82, 3725–3735 (2008).

    Article  CAS  Google Scholar 

  18. Hirsch, V.M. et al. Induction of AIDS by simian immunodeficiency virus from an African green monkey: species-specific variation in pathogenicity correlates with the extent of in vivo replication. J. Virol. 69, 955–967 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Goldstein, S. et al. Plateau levels of viremia correlate with the degree of CD4+-T-cell loss in simian immunodeficiency virus SIVagm-infected pigtailed macaques: variable pathogenicity of natural SIVagm isolates. J. Virol. 79, 5153–5162 (2005).

    Article  CAS  Google Scholar 

  20. 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  PubMed Central  Google Scholar 

  21. Hirsch, V. et al. A molecularly cloned, pathogenic, neutralization-resistant simian immunodeficiency virus, SIVsmE543–3. J. Virol. 71, 1608–1620 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Li, Y. et al. Complete nucleotide sequence, genome organization and biological properties of human immunodeficiency virus type 1 in vivo: evidence for limited defectiveness and complementation. J. Virol. 66, 6587–6600 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Fultz, P.N., McClure, H.M., Anderson, D.C. & Switzer, W.M. Identification and biologic 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 

  24. Giorgi, J.V. et al. Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J. Infect. Dis. 179, 859–870 (1999).

    Article  CAS  Google Scholar 

  25. Chakrabarti, L.A. et al. Normal T-cell turnover in sooty mangabeys harboring active simian immunodeficiency virus infection. J. Virol. 74, 1209–1223 (2000).

    Article  CAS  Google Scholar 

  26. Sumpter, B. et al. Correlates of preserved CD4+ T-cell homeostasis during natural, nonpathogenic simian immunodeficiency virus infection of sooty mangabeys: implications for AIDS pathogenesis. J. Immunol. 178, 1680–1691 (2007).

    Article  CAS  Google Scholar 

  27. Pandrea, I. et al. High levels of SIVmnd-1 replication in chronically infected Mandrillus sphinx. Virology 317, 119–127 (2003).

    Article  CAS  Google Scholar 

  28. Pandrea, I.V. et al. Acute loss of intestinal CD4+ T cells is not predictive of simian immunodeficiency virus virulence. J. Immunol. 179, 3035–3046 (2007).

    Article  CAS  Google Scholar 

  29. Murayama, Y., Mukai, R., Inoue-Murayama, M. & Yoshikawa, Y. An African green monkey lacking peripheral CD4 lymphocytes that retains helper T-cell activity and coexists with SIVagm. Clin. Exp. Immunol. 117, 504–512 (1999).

    Article  CAS  Google Scholar 

  30. Murayama, Y. et al. CD4 and CD8 expressions in African green monkey helper T lymphocytes: implication for resistance to SIV infection. Int. Immunol. 9, 843–851 (1997).

    Article  CAS  Google Scholar 

  31. Banchereau, J. et al. The CD40 antigen and its ligand. Annu. Rev. Immunol. 12, 881–922 (1994).

    Article  CAS  Google Scholar 

  32. Karube, K. et al. Expression of FoxP3, a key molecule in CD4CD25 regulatory T cells, in adult T-cell leukaemia/lymphoma cells. Br. J. Haematol. 126, 81–84 (2004).

    Article  CAS  Google Scholar 

  33. 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. Nat. Med. 5, 518–525 (1999).

    Article  CAS  Google Scholar 

  34. Brenchley, J.M. et al. T-cell subsets that harbor human immunodeficiency virus (HIV) in vivo: implications for HIV pathogenesis. J. Virol. 78, 1160–1168 (2004).

    Article  CAS  Google Scholar 

  35. Brenchley, J.M. et al. Differential TH17 CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections. Blood 112, 2826–2835 (2008).

    Article  CAS  Google Scholar 

  36. Gordon, S.N. et al. Severe depletion of mucosal CD4+ T cells in AIDS-free simian immunodeficiency virus–infected sooty mangabeys. J. Immunol. 179, 3026–3034 (2007).

    Article  CAS  Google Scholar 

  37. Pandrea, I. et al. Paucity of CD4+CCR5+ T cells is a typical feature of natural SIV hosts. Blood 109, 1069–1076 (2007).

    Article  CAS  Google Scholar 

  38. Hunt, P.W. et al. Relationship between T-cell activation and CD4+ T-cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J. Infect. Dis. 197, 126–133 (2008).

    Article  Google Scholar 

  39. Jiang, W. et al. Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral-treated HIV infection. J. Infect. Dis. 199, 1177–1185 (2009).

    Article  CAS  Google Scholar 

  40. Papasavvas, E. et al. Delayed loss of control of plasma lipopolysaccharide levels after therapy interruption in chronically HIV-1–infected patients. AIDS 23, 369–375 (2009).

    Article  CAS  Google Scholar 

  41. Gregson, J.N. et al. Elevated plasma lipopolysaccharide is not sufficient to drive natural killer cell activation in HIV-1–infected individuals. AIDS 23, 29–34 (2009).

    Article  CAS  Google Scholar 

  42. Brenchley, J.M. et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat. Med. 12, 1365–1371 (2006).

    Article  CAS  Google Scholar 

  43. Ancuta, P. et al. Microbial translocation is associated with increased monocyte activation and dementia in AIDS patients. PLoS One 3, e2516 (2008).

    Article  Google Scholar 

  44. Balagopal, A. et al. Human immunodeficiency virus–related microbial translocation and progression of hepatitis C. Gastroenterology 135, 226–233 (2008).

    Article  CAS  Google Scholar 

  45. Marchetti, G. et al. Microbial translocation is associated with sustained failure in CD4+ T-cell reconstitution in HIV-infected patients on long-term highly active antiretroviral therapy. AIDS 22, 2035–2038 (2008).

    Article  CAS  Google Scholar 

  46. Boulassel, M.R., Mercier, F., Gilmore, N. & Routy, J.P. Immunophenotypic patterns of CD8+ T-cell subsets expressing CD8αα and IL-7Rα in viremic, aviremic and slow progressor HIV-1–infected subjects. Clin. Immunol. 124, 149–157 (2007).

    Article  CAS  Google Scholar 

  47. Rahemtulla, A. et al. Normal development and function of CD8+ cells but markedly decreased helper cell activity in mice lacking CD4. Nature 353, 180–184 (1991).

    Article  CAS  Google Scholar 

  48. Rahemtulla, A. et al. Class II major histocompatibility complex–restricted T-cell function in CD4-deficient mice. Eur. J. Immunol. 24, 2213–2218 (1994).

    Article  CAS  Google Scholar 

  49. Barber, E.K., Dasgupta, J.D., Schlossman, S.F., Trevillyan, J.M. & Rudd, C.E. The CD4 and CD8 antigens are coupled to a protein-tyrosine kinase (p56lck) that phosphorylates the CD3 complex. Proc. Natl. Acad. Sci. USA 86, 3277–3281 (1989).

    Article  CAS  Google Scholar 

  50. Matsunaga, S., Mukai, R., Inoue-Murayama, M., Yoshikawa, Y. & Murayama, Y. Sequence and functional properties of African green monkey CD4 silencer. Immunol. Lett. 75, 47–53 (2000).

    Article  CAS  Google Scholar 

  51. Kioussis, D. & Ellmeier, W. Chromatin and CD4, CD8A and CD8B gene expression during thymic differentiation. Nat. Rev. Immunol. 2, 909–919 (2002).

    Article  CAS  Google Scholar 

  52. Bilic, I. et al. Negative regulation of CD8 expression via Cd8 enhancer–mediated recruitment of the zinc finger protein MAZR. Nat. Immunol. 7, 392–400 (2006).

    Article  CAS  Google Scholar 

  53. Milush, J.M. et al. Virally induced CD4+ T-cell depletion is not sufficient to induce AIDS in a natural host. J. Immunol. 179, 3047–3056 (2007).

    Article  CAS  Google Scholar 

  54. Roelke, M.E. et al. T-lymphocyte profiles in FIV-infected wild lions and pumas reveal CD4 depletion. J. Wildl. Dis. 42, 234–248 (2006).

    Article  CAS  Google Scholar 

  55. Mattapallil, J.J. et al. Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection. Nature 434, 1093–1097 (2005).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

These studies were supported by the intramural National Institute of Allergy and Infectious Diseases, US National Institutes of Health program and by R01 AI064066 (I.P.), R01 AI065325 (C.A.) and RR-00168 (Tulane National Primate Center). We would like to thank the Bad Boys of Cleveland, D. Douek (Vaccine Research Center, National Institute of Allergy and Infectious Diseases, US National Institutes of Health) and D. Price (Cardiff University) for helpful discussions. We are grateful to J.E. Schmitz and R. Zahn (Harvard University) for the kind donation of microbeads coated with antibody to CD3 and CD28 for stimulation of T cells from nonhuman primates. We also appreciate the technical advice of B. Lafont and G. Mettler.

Author information

Authors and Affiliations

Authors

Contributions

C.M.B., L.D.H., N.R.K., S.W., J.M. and J.M.B. performed experiments and analyzed the data. S.G., C.A., I.P. and V.M.H. provided specimens and analyzed data. All authors contributed to the project's planning and writing of the manuscript. J.M.B. supervised the project.

Corresponding author

Correspondence to Jason M Brenchley.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1–3 (PDF 1185 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Beaumier, C., Harris, L., Goldstein, S. et al. CD4 downregulation by memory CD4+ T cells in vivo renders African green monkeys resistant to progressive SIVagm infection. Nat Med 15, 879–885 (2009). https://doi.org/10.1038/nm.1970

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.1970

This article is cited by

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