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Low levels of SIV infection in sooty mangabey central memory CD4+ T cells are associated with limited CCR5 expression

Nature Medicine volume 17, pages 830–836 (2011)Cite this article

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Abstract

Naturally simian immunodeficiency virus (SIV)-infected sooty mangabeys do not progress to AIDS despite high-level virus replication. We previously showed that the fraction of CD4+CCR5+ T cells is lower in sooty mangabeys compared to humans and macaques. Here we found that, after in vitro stimulation, sooty mangabey CD4+ T cells fail to upregulate CCR5 and that this phenomenon is more pronounced in CD4+ central memory T cells (TCM cells). CD4+ T cell activation was similarly uncoupled from CCR5 expression in sooty mangabeys in vivo during acute SIV infection and the homeostatic proliferation that follows antibody-mediated CD4+ T cell depletion. Sooty mangabey CD4+ TCM cells that express low amounts of CCR5 showed reduced susceptibility to SIV infection both in vivo and in vitro when compared to CD4+ TCM cells of rhesus macaques. These data suggest that low CCR5 expression on sooty mangabey CD4+ T cells favors the preservation of CD4+ T cell homeostasis and promotes an AIDS-free status by protecting CD4+ TCM cells from direct virus infection.

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Figure 1: The fraction of CCR5+ cells ex vivo is significantly lower in all subsets of CD4+ T cells of sooty mangabeys as compared to rhesus macaques.
Figure 2: CCR5 expression upon in vitro activation and proliferation is significantly lower in CD4+ T cells of sooty mangabeys than rhesus macaques.
Figure 3: The fraction of CD4+CCR5+ T cells upon in vivo activation is significantly lower in sooty mangabeys as compared to rhesus macaques.
Figure 4: Lower fraction of CCR5+ cells after in vitro activation of sorted CD4+ TCM cells of sooty mangabeys as compared to rhesus macaques.
Figure 5: CD4+ TCM of sooty mangabeys are relatively resistant to SIV infection in vivo.
Figure 6: CD4+ TCM of sooty mangabeys are relatively resistant to SIV infection in vitro.

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Acknowledgements

We wish to thank L. Picker, D. Sodora and Z. Grossman for helpful discussions; F. Villinger, B. Lawson, F. Shaheen and J. Tilton for their technical support; and S. Ehnert and T. Meeker for their assistance with primate studies. We are grateful to the Emory Center for AIDS Research Virology Core and the Penn Center for AIDS Research Virology Core for their assistance. This work was supported by grant R01-AI66998 and P01-AI76074 (to G.S.), R56-AI087186 (to M.P.) and P51-RR-00165 (to Yerkes National Primate Research Center).

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  1. Mirko Paiardini and Barbara Cervasi: These authors contributed equally to this work.

Authors and Affiliations

  1. Emory Vaccine Center and Department of Pathology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA

    Mirko Paiardini, Barbara Cervasi, Luca Micci, Alexandra M Ortiz, Ann Chahroudi, Shari N Gordon, Steven E Bosinger, James Else & Guido Silvestri

  2. Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    Mirko Paiardini, Barbara Cervasi, Elane Reyes-Aviles, Alexandra M Ortiz, Shari N Gordon, Nicholas Francella, Paul L Hallberg, Elizabeth Cramer & Guido Silvestri

  3. University of Urbino, Urbino, Italy

    Luca Micci

  4. Laboratory of Molecular Microbiology, US National Institutes of Health, Bethesda, Maryland, USA

    Carol Vinton & Jason M Brenchley

  5. Complex Systems in Biology Group, Centre for Vascular Research, University of New South Wales, Kensington, New South Wales, Australia

    Timothy Schlub, Ming Liang Chan & Miles P Davenport

  6. Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    Nadeene E Riddick & Ronald G Collman

  7. Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Cristian Apetrei & Ivona Pandrea

  8. Institute of Molecular Virology, University Hospital Ulm, Ulm, Germany

    Jan Munch & Frank Kirchhoff

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Contributions

M.P., B.C. and G.S. designed the study and wrote the paper, with contributions from the other authors as appropriate; M.P., B.C. and E.R.-A. performed the immunophenotypic analyses, analyzed results and prepared the figures; L.M., A.M.O., E.C. and A.C. helped in preparing the reagents, processing the samples and analyzing the data; C.V. and J.M.B. performed the quantitative PCR for SIV gag DNA; S.N.G. provided the data on experimentally SIV-infected sooty mangabeys and rhesus macaques; S.E.B. and N.F. determined CCR5 mRNA levels; P.L.H. performed the sorting experiments; T.S., M.L.C. and M.P.D. contributed to the design of the study and statistical analyses; J.E. supervised the housing and care of the primates and contributed to the design of the study and sample collection; J.M. and F.K. provided the eGFP-expressing SIV reporter virus; C.A., I.P., N.E.R., F.K. and R.G.C. contributed to the study design and preparation of the manuscript.

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Correspondence to Mirko Paiardini or Guido Silvestri.

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Paiardini, M., Cervasi, B., Reyes-Aviles, E. et al. Low levels of SIV infection in sooty mangabey central memory CD4+ T cells are associated with limited CCR5 expression. Nat Med 17, 830–836 (2011). https://doi.org/10.1038/nm.2395

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