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

Nature Medicine volume 15, pages 879–885 (2009)Cite this article

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.

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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: CD4−CD8αdim T cells can develop from memory CD4+ T cells.
Figure 4: CD4−CD8αdim T cells can preserve CD4+ T-cell function.
Figure 5: Infection frequencies of lymphocyte subsets.

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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.

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Authors and Affiliations

  1. Lab of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA

    Coreen M Beaumier, Levelle D Harris, Simoy Goldstein, Nichole R Klatt, Sonya Whitted, John McGinty, Vanessa M Hirsch & Jason M Brenchley

  2. Divisions of Comparative Pathology and Microbiology, Tulane National Primate Center, New Orleans, Louisiana, USA

    Cristian Apetrei & Ivona Pandrea

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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.

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Correspondence to Jason M Brenchley.

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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

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