HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation

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Abstract

HIV persists in a reservoir of latently infected CD4+ T cells in individuals treated with highly active antiretroviral therapy (HAART). Here we identify central memory (TCM) and transitional memory (TTM) CD4+ T cells as the major cellular reservoirs for HIV and find that viral persistence is ensured by two different mechanisms. HIV primarily persists in TCM cells in subjects showing reconstitution of the CD4+ compartment upon HAART. This reservoir is maintained through T cell survival and low-level antigen-driven proliferation and is slowly depleted with time. In contrast, proviral DNA is preferentially detected in TTM cells from aviremic individuals with low CD4+ counts and higher amounts of interleukin-7–mediated homeostatic proliferation, a mechanism that ensures the persistence of these cells. Our results suggest that viral eradication might be achieved through the combined use of strategic interventions targeting viral replication and, as in cancer, drugs that interfere with the self renewal and persistence of proliferating memory T cells.

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Figure 1: Integrated DNA is the major molecular form of HIV during HAART and is harbored by TCM and TTM cells in vivo.
Figure 2: CD4+ T cell depletion drives the size and the localization of the HIV reservoir.
Figure 3: Proliferation of CD4+ T cells drives the size and the localization of the HIV reservoir.
Figure 4: TCM and TTM cells define a distinct HIV reservoir.
Figure 5: Proliferation of TTM cells is associated with a genetic stability of the HIV reservoir over time.
Figure 6: IL-7 induces homeostatic proliferation of CD4+ T cells and ensures HIV reservoir stability through cellular proliferation at low levels.

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Acknowledgements

We thank the study subjects for their participation in this study. We also thank M. Legault and C. Grignon for clinical assistance with subjects, N. Kettaf, M. Lainesse, V. Lafontaine and Y. Chouikh for technical assistance, S. Gimmig and L. Lejeune for flow cytometric cell sorting and T. Sing for assistance with the co-receptor prediction software. We are grateful to E. Hunter for his expertise in phylogenetic analyses. N.C. is supported by the American Foundation for AIDS Research (amfAR, fellowship number 106634-38-RFRL). M.E. and L.T. are funded by the Canadian Institutes of Health Research. J.P.R., is a clinician-scientist supported by Fonds de la Recherche en Santé du Québec (FRSQ). R.-P.S. is the Canada Research Chair in Human Immunology. This study was supported by funds from amfAR (grants 106-722-40-RGRL, 106-847-42-RGRL and 107-175-44-RGRL), CANFAR (grant 18008), the US National Institutes of Health, the Canadian Institutes of Health Research, the Canadian HIV Trials Network, Vaccines and Immunotherapeutics core and the Réseau FRSQ-SIDA/maladies infectieuses.

Author information

N.C. planned and performed the experiments, analyzed the data and wrote the manuscript. M.E. and F.A.P. assisted with the cell sorting and quantification experiments. P.A., L.T. and B.Y.-D. helped with the flow cytometry experiments and with writing the manuscript. M.-R.B., G.G., J.M.B., T.W.S. and J.-P.R. provided samples from research subjects. J.-P.R. helped with writing the manuscript. M.-R.B. perfomed interleukin-7 measurements. G.B. did the co-receptor prediction usage analysis. B.J.H. and D.C.D. performed lipopolysaccharide measurements. E.K.H. and R.-P.S. planned and supervised all experiments and wrote the manuscript.

Correspondence to Rafick-Pierre Sékaly.

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Chomont, N., El-Far, M., Ancuta, P. et al. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med 15, 893–900 (2009) doi:10.1038/nm.1972

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