The anti-caspase inhibitor Q-VD-OPH prevents AIDS disease progression in SIV-infected rhesus macaques

• Type of Material: Article
• Authors: Mireille Laforge, Université Paris Descartes; Ricardo Silvestre, Université Paris Descartes; Vasco Rodrigues, Université Paris Descartes; Julie Garibal, Université Paris Descartes; Laure Campillo-Gimenez, Université Paris Descartes; Shahul Mouhamad, Université Paris Descartes; Valérie Monceaux, Institut Pasteur; Marie-Christine Cumont, Institut Pasteur; Henintsoa Rabezanahary, Université Laval; Alain Pruvost, Laboratoire d’Etude du Métabolisme des Médicaments; Anabela Cordeiro-da-Silva, Universidade do Porto; Bruno Hurtrel, Institut Pasteur; Guido Silvestri, Emory University; Anna Senik, Université Paris Descartes; Jérôme Estaquier, Université Paris Descartes
• Language: English
• Date: 2018-04-01
• Publisher: American Society for Clinical Investigation
• Publication Version: Final Published Version
• Copyright Statement: © 2018 American Society for Clinical Investigation. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1172/JCI95127
• Title of Journal or Parent Work: Journal of Clinical Investigation
• ISSN: 0021-9738
• Volume: 128
• Issue: 4
• Start Page: 1627
• End Page: 1640
• Grant/Funding Information: JE thanks the Canada Research Chair program for financial assistance.; This study was supported by research funding from ANRS and CIHR (MOP-133476) to JE.; RS thanks Fundação para a Ciência e a Tecnologia (FCT) for Investigator FCT Grant IF/0002 1/2014.; VR is supported by a fellowship from FCT (code SFRH/BD/64064/2009).; ML and JG were supported by fellowships from ANRS.
• Keywords: HIV-1 INFECTION; Medicine, Research & Experimental; MEMBRANE PERMEABILIZATION; Science & Technology; PLASMA VIRAL LOAD; Research & Experimental Medicine; GAMMA-INDUCING FACTOR; PRIMARY CD4+T CELLS; ACTIVE ANTIRETROVIRAL THERAPY; Life Sciences & Biomedicine; SIMIAN IMMUNODEFICIENCY VIRUS; CD4(+) T-CELLS; FAS-MEDIATED APOPTOSIS; LYMPH-NODES
• Research Categories: Biology, Molecular; Biology, Microbiology

Abstract

Apoptosis has been proposed as a key mechanism responsible for CD4+ T cell depletion and immune dysfunction during HIV infection. We demonstrated that Q-VD-OPH, a caspase inhibitor, inhibits spontaneous and activation-induced death of T cells from SIV-infected rhesus macaques (RMs). When administered during the acute phase of infection, Q-VD-OPH was associated with (a) reduced levels of T cell death, (b) preservation of CD4+/CD8+ T cell ratio in lymphoid organs and in the gut, (c) maintenance of memory CD4+ T cells, and (d) increased specific CD4+ T cell response associated with the expression of cytotoxic molecules. Although therapy was limited to the acute phase of infection, Q-VD-OPH-treated RMs showed lower levels of both viral load and cell-associated SIV DNA as compared with control SIV-infected RMs throughout the chronic phase of infection, and prevented the development of AIDS. Overall, our data demonstrate that Q-VD-OPH injection in SIV-infected RMs may represent an adjunctive therapeutic agent to control HIV infection and delaying disease progression to AIDS.