Interleukin-21 combined with ART reduces inflammation and viral reservoir in SIV-infected macaques

• Type of Material: Article
• Authors: Luca Micci, Emory University; Emily S. Ryan, Emory University; Rémi Fromentin, Université de Montréal; Steven Bosinger, Emory University; Justin L. Harper, Emory University; Tianyu He, University of Pittsburgh; Sara Paganini, Emory University; Kirk Easley, Emory University; Ann Chahroudi, Emory University; Clarisse Benne, Case Western Reserve University; Sanjeev Gumber, Emory University; Colleen S. McGary, Emory University; Kenneth A. Rogers, Emory University; Claire Deleage, Frederick National Laboratory for Cancer Research; Carissa Lucero, Frederick National Laboratory for Cancer Research; Siddappa Byrareddy, Emory University; Cristian Apetrei, University of Pittsburgh; Jacob D. Estes, Frederick National Laboratory for Cancer Research; Jeffrey D. Lifson, Frederick National Laboratory for Cancer Research; Michael Piatak, Jr., Frederick National Laboratory for Cancer Research; Nicolas Chomont, Université de Montréal; Francois Villinger, Emory University; Guido Silvestri, Emory University; Jason M. Brenchley, National Institute of Allergy and Infectious Diseases (NIAID); Mirko Paiardini, Emory University
• Language: English
• Date: 2015-12-01
• Publisher: American Society for Clinical Investigation
• Publication Version: Final Published Version
• Copyright Statement: © 2015, American Society for Clinical Investigation
• Final Published Version (URL): http://dx.doi.org/10.1172/JCI81400
• Title of Journal or Parent Work: Journal of Clinical Investigation
• ISSN: 0021-9738
• Volume: 125
• Issue: 12
• Start Page: 4497
• End Page: 4513
• Grant/Funding Information: Research reported in this publication was supported by the NIAID, NIH under award numbers R01AI116379, R01AI110334, and R33AI104278 (to M. Paiardini), ORIP/OD P51OD011132 (formerly NCRR P51RR000165, to the YNPRC), ORIP/OD 5R24RR016988 and P30AI50409 (to the Emory Center for AIDS Research), as well as by amfAR grant 109109-57-RGRL (to M. Paiardini).; This project has been supported in part by federal funds from the National Cancer Institute, NIH, under contract HHSN261200800001E, as well as by the Division of Intramural Research, NIAID, NIH (A1001029).
• Keywords: PHASE-I TRIAL; CHRONIC HIV-INFECTION; IMMUNE ACTIVATION; T(H)17 CELLS; RHESUS MACAQUES; Life Sciences & Biomedicine; PLASMA-CELLS; SOOTY MANGABEY; Science & Technology; CD4(+) T-CELLS; Research & Experimental Medicine; METASTATIC MELANOMA; Medicine, Research & Experimental; ACTIVE ANTIRETROVIRAL THERAPY
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Medicine and Surgery

Abstract

Despite successful control of viremia, many HIV-infected individuals given antiretroviral therapy (ART) exhibit residual inflammation, which is associated with non-AIDS-related morbidity and mortality and may contribute to virus persistence during ART. Here, we investigated the effects of IL-21 administration on both inflammation and virus persistence in ARTtreated, SIV-infected rhesus macaques (RMs). Compared with SIV-infected animals only given ART, SIV-infected RMs given both ART and IL-21 showed improved restoration of intestinal Th17 and Th22 cells and a more effective reduction of immune activation in blood and intestinal mucosa, with the latter maintained through 8 months after ART interruption. Additionally, IL-21, in combination with ART, was associated with reduced levels of SIV RNA in plasma and decreased CD4+ T cell levels harboring replication-competent virus during ART. At the latest experimental time points, which were up to 8 months after ART interruption, plasma viremia and cell-associated SIV DNA levels remained substantially lower than those before ART initiation in IL-21-treated animals but not in controls. Together, these data suggest that IL-21 supplementation of ART reduces residual inflammation and virus persistence in a relevant model of lentiviral disease and warrants further investigation as a potential intervention for HIV infection.