CTLA-4(+)PD-1(-) Memory CD4(+) T Cells Critically Contribute to Viral Persistence in Antiretroviral Therapy-Suppressed, SIV-Infected Rhesus Macaques

Author:

McGary, Colleen S

Deleage, Claire

Harper, Justin

Micci, Luca

Ribeiro, Susan P

Paganini, Sara

Kuri-Cervantes, Leticia

Benne, Clarisse

Ryan, Emily S

Balderas, Robert

Jean, Sherrie

Easley, Kirk

Marconi, Vincent

Silvestri, Guido

Estes, Jake

Sekaly, Rafick-Pierre

Paiardini, Mirko
Author Address

Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA., AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA., Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA., Becton Dickinson Immunosciences, San Jose, CA 95131, USA., Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Atlanta, GA 30329, USA., Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA; Department of Medicine, Emory University School of Medicine, Atlanta, GA 30329, USA., Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA; Department of Medicine, Emory University School of Medicine, Atlanta, GA 30329, USA. Electronic address: mirko.paiardini@emory.edu.,

Abstract:

Antiretroviral therapy (ART) suppresses viral replication in HIV-infected individuals but does not eliminate the reservoir of latently infected cells. Recent work identified PD-1(+) follicular helper T (Tfh) cells as an important cellular compartment for viral persistence. Here, using ART-treated, SIV-infected rhesus macaques, we show that CTLA-4(+)PD-1(-) memory CD4(+) T cells, which share phenotypic markers with regulatory T cells, were enriched in SIV DNA in blood, lymph nodes (LN), spleen, and gut, and contained replication-competent and infectious virus. In contrast to PD-1(+) Tfh cells, SIV-enriched CTLA-4(+)PD-1(-) CD4(+) T cells were found outside the B cell follicle of the LN, predicted the size of the persistent viral reservoir during ART, and significantly increased their contribution to the SIV reservoir with prolonged ART-mediated viral suppression. We have shown that CTLA-4(+)PD-1(-) memory CD4(+) T cells are a previously unrecognized component of the SIV and HIV reservoir that should be therapeutically targeted for a functional HIV-1 cure. Copyright © 2017 Elsevier Inc. All rights reserved.

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