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

Nicolas Chomont; Mohamed El-Far; Petronela Ancuta; Lydie Trautmann; Francesco A. Procopio; Bader Yassine-Diab; Geneviève Boucher; Mohamed Rachid Boulassel; Georges Ghattas; Jason M. Brenchley; Timothy W. Schacker; Brenna J. Hill; Daniel C. Douek; Jean Pierre Routy; Elias K. Haddad; Rafick Pierre Sékaly

doi:10.1038/nm.1972

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

Nicolas Chomont, Mohamed El-Far, Petronela Ancuta, Lydie Trautmann, Francesco A. Procopio, Bader Yassine-Diab, Geneviève Boucher, Mohamed Rachid Boulassel, Georges Ghattas, Jason M. Brenchley, Timothy W. Schacker, Brenna J. Hill, Daniel C. Douek, Jean Pierre Routy, Elias K. Haddad, Rafick Pierre Sékaly

Medicine - Infectious Disease and International

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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 (T(CM)) and transitional memory (T(TM)) 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 T(CM) 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 T(TM) 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.

Original language	English (US)
Pages (from-to)	893-900
Number of pages	8
Journal	Nature Medicine
Volume	15
Issue number	8
DOIs	https://doi.org/10.1038/nm.1972
State	Published - Aug 2009

Bibliographical note

Funding Information:
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.

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Chomont, N., El-Far, M., Ancuta, P., Trautmann, L., Procopio, F. A., Yassine-Diab, B., Boucher, G., Boulassel, M. R., Ghattas, G., Brenchley, J. M., Schacker, T. W., Hill, B. J., Douek, D. C., Routy, J. P., Haddad, E. K., & Sékaly, R. P. (2009). HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nature Medicine, 15(8), 893-900. https://doi.org/10.1038/nm.1972

Chomont, N, El-Far, M, Ancuta, P, Trautmann, L, Procopio, FA, Yassine-Diab, B, Boucher, G, Boulassel, MR, Ghattas, G, Brenchley, JM, Schacker, TW, Hill, BJ, Douek, DC, Routy, JP, Haddad, EK & Sékaly, RP 2009, 'HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation', Nature Medicine, vol. 15, no. 8, pp. 893-900. https://doi.org/10.1038/nm.1972

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title = "HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation",

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 (T(CM)) and transitional memory (T(TM)) 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 T(CM) 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 T(TM) 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.",

author = "Nicolas Chomont and Mohamed El-Far and Petronela Ancuta and Lydie Trautmann and Procopio, {Francesco A.} and Bader Yassine-Diab and Genevi{\`e}ve Boucher and Boulassel, {Mohamed Rachid} and Georges Ghattas and Brenchley, {Jason M.} and Schacker, {Timothy W.} and Hill, {Brenna J.} and Douek, {Daniel C.} and Routy, {Jean Pierre} and Haddad, {Elias K.} and S{\'e}kaly, {Rafick Pierre}",

note = "Funding Information: 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 Sant{\'e} du Qu{\'e}bec (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 R{\'e}seau FRSQ-SIDA/maladies infectieuses.",

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AU - Yassine-Diab, Bader

AU - Boucher, Geneviève

AU - Boulassel, Mohamed Rachid

AU - Ghattas, Georges

AU - Brenchley, Jason M.

AU - Schacker, Timothy W.

AU - Hill, Brenna J.

AU - Douek, Daniel C.

AU - Routy, Jean Pierre

AU - Haddad, Elias K.

AU - Sékaly, Rafick Pierre

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N2 - 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 (T(CM)) and transitional memory (T(TM)) 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 T(CM) 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 T(TM) 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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HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation

Abstract

Bibliographical note

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