A Highly Intensified ART Regimen Induces Long-Term Viral Suppression and Restriction of the Viral Reservoir in a Simian AIDS Model

PLoS Pathogens

Jack Greenhouse¹  Matt Collins¹  Jake Yalley-Ogunro¹  Mark G. Lewis¹  Iart Luca Shytaj²  Sandro Norelli²  Barbara Chirullo²  Alessandro Della Corte²  Andrea Savarino²  Maria Letizia Barreca³  Nunzio Iraci³  Edward P. Acosta⁴ 

[1] BIOQUAL, Inc., Rockville, Maryland, United States of America;Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, Rome, Italy;Dipartimento di Chimica e Tecnologia del Farmaco, Facoltà di Farmacia, Università di Perugia, Perugia, Italy;The University of Alabama at Birmingham, Division of Clinical Pharmacology, Birmingham, Alabama, United States of America

关键词: Macaque;    Viral load;    T cells;    Antiretroviral therapy;    Viral replication;    Memory T cells;    Viremia;    Drug therapy;   

DOI  :  10.1371/journal.ppat.1002774

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Stably suppressed viremia during ART is essential for establishing reliable simian models for HIV/AIDS. We tested the efficacy of a multidrug ART (highly intensified ART) in a wide range of viremic conditions (103–107 viral RNA copies/mL) in SIVmac251-infected rhesus macaques, and its impact on the viral reservoir. Eleven macaques in the pre-AIDS stage of the disease were treated with a multidrug combination (highly intensified ART) consisting of two nucleosidic/nucleotidic reverse transcriptase inhibitors (emtricitabine and tenofovir), an integrase inhibitor (raltegravir), a protease inhibitor (ritonavir-boosted darunavir) and the CCR5 blocker maraviroc. All animals stably displayed viral loads below the limit of detection of the assay (i.e. <40 RNA copies/mL) after starting highly intensified ART. By increasing the sensitivity of the assay to 3 RNA copies/mL, viral load was still below the limit of detection in all subjects tested. Importantly, viral DNA resulted below the assay detection limit (<2 copies of DNA/5*105 cells) in PBMCs and rectal biopsies of all animals at the end of the follow-up, and in lymph node biopsies from the majority of the study subjects. Moreover, highly intensified ART decreased central/transitional memory, effector memory and activated (HLA-DR+) effector memory CD4+ T-cells in vivo, in line with the role of these subsets as the main cell subpopulations harbouring the virus. Finally, treatment with highly intensified ART at viral load rebound following suspension of a previous anti-reservoir therapy eventually improved the spontaneous containment of viral load following suspension of the second therapeutic cycle, thus leading to a persistent suppression of viremia in the absence of ART. In conclusion, we show, for the first time, complete suppression of viral load by highly intensified ART and a likely associated restriction of the viral reservoir in the macaque AIDS model, making it a useful platform for testing potential cures for AIDS.

【 授权许可】

CC BY