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*Department of Microbiology and Immunology, Université de Montréal;
Centre de Recherche du Research Centre, Centre Hospitalier de l’Université de Montréal, Saint-Luc Hospital;
The French National Institute of Health and Medical Research Unit 743;
¶Division of Hematology and
||Immunodeficiency Service, Montreal Chest Institute, McGill University Health Centre, Montreal, Quebec, Canada; and
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115
There is limited knowledge on the identity of primary CD4+ T cell subsets selectively targeted by HIV-1 in vivo. In this study, we established a link between HIV permissiveness, phenotype/homing potential, and lineage commitment in primary CD4+ T cells. CCR4+CCR6+, CCR4+CCR6–, CXCR3+CCR6+, and CXCR3+CCR6– T cells expressed cytokines and transcription factors specific for Th17, Th2, Th1Th17, and Th1 lineages, respectively. CCR4+CCR6+ and CXCR3+CCR6+ T cells expressed the HIV coreceptors CCR5 and CXCR4 and were permissive to R5 and X4 HIV replication. CCR4+CCR6– T cells expressed CXCR4 but not CCR5 and were permissive to X4 HIV only. CXCR3+CCR6– T cells expressed CCR5 and CXCR4 but were relatively resistant to R5 and X4 HIV in vitro. Total CCR6+ T cells compared with CCR6– T cells harbored higher levels of integrated HIV DNA in treatment-naive HIV-infected subjects. The frequency of total CCR6+ T cells and those of CCR4+CCR6+ and CXCR3+CCR6+ T cells were diminished in chronically infected HIV-positive subjects, despite viral-suppressive therapy. A high-throughput analysis of cytokine profiles identified CXCR3+CCR6+ T cells as a major source of TNF-
and CCL20 and demonstrated a decreased TNF-/IL-10 ratio in CXCR3+CCR6– T cells. Finally, CCR4+CCR6+ and CXCR3+CCR6+ T cells exhibited gut- and lymph node-homing potential. Thus, we identified CCR4+CCR6+ and CXCR3+CCR6+ T cells as highly permissive to HIV replication, with potential to infiltrate and recruit more CCR6+ T cells into anatomic sites of viral replication. It is necessary that new therapeutic strategies against HIV interfere with viral replication/persistence in discrete CCR6+ T cell subsets.
Address correspondence and reprint requests to Dr. Petronela Ancuta, Centre de Recherche du Research Centre, Centre Hospitalier de l’Université de Montréal, Saint-Luc Hospital, Pavillon Edouard Asselin, Room 411, 264 Boulevard René-Lévesque East, Montreal, QC H2X 1P1, Canada. E-mail address: petronela.ancuta{at}umontreal.ca.
1 A.G. and P.M. contributed equally to this work.
This work was supported in part by grants to P.A. from the Canadian Institutes of Health Research (CIHR) (MOP-82849), Fondation du Centre Hospitalier de l’Université de Montréal, Fonds de la Recherche en Santé Québec (FRSQ), the French National Institute of Health and Medical Research (INSERM), National Agency for AIDS Research (ANRS), Agence Nationale de Recherche sur le SIDA, and Fondation de France. P.A. was supported by New Investigator awards from FRSQ and INSERM. P.M., N.C., E.A.S., and M.E.F. were supported by postdoctoral fellowships from ANRS, Fondation de France, FRSQ, The Foundation for AIDS Research, and CIHR, respectively. Core facilities were supported by the Fondation du Centre Hospitalier de l’Université de Montréal and the FRSQ AIDS-Infectious Diseases Network.
The online version of this article contains supplemental material.
Abbreviations used in this paper:
ART, antiretroviral therapy; CI on ART, chronically infected under long-term antiretroviral therapy; LTR, long terminal repeat; NA, not available; RI w/o ART, recently HIV-infected treatment-naïve; T-bet, T-box expressed in T cells; Treg, regulatory T cell.
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