A highly intensified ART regimen induces long-term viral suppression and restriction of the viral reservoir in a simian AIDS model.
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.
Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, Rome, Italy.
Iart Luca
IL
Shytaj
Sandro
S
Norelli
Barbara
B
Chirullo
Alessandro
A
Della Corte
Matt
M
Collins
Jake
J
Yalley-Ogunro
Jack
J
Greenhouse
Nunzio
N
Iraci
Edward P
EP
Acosta
Maria Letizia
ML
Barreca
Mark G
MG
Lewis
Andrea
A
Savarino
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D003510:Cyclohexanes / Q000008:administration & dosage; D000069454:Darunavir; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004359:Drug Therapy, Combination; D000068679:Emtricitabine; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D008253:Macaca mulatta; D000077592:Maraviroc; D063065:Organophosphonates / Q000008:administration & dosage; D011760:Pyrrolidinones / Q000008:administration & dosage; D000068898:Raltegravir Potassium; D019438:Ritonavir / Q000008:administration & dosage; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D013449:Sulfonamides / Q000008:administration & dosage; D016176:T-Lymphocyte Subsets / Q000187:drug effects*; D000068698:Tenofovir; D014230:Triazoles / Q000008:administration & dosage; D019562:Viral Load / Q000187:drug effects*; D014766:Viremia / Q000188:drug therapy
D019380:Anti-HIV Agents; D003510:Cyclohexanes; D063065:Organophosphonates; D011760:Pyrrolidinones; D013449:Sulfonamides; D014230:Triazoles; D003841:Deoxycytidine; D000068898:Raltegravir Potassium; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine; D000077592:Maraviroc; D019438:Ritonavir; D000069454:Darunavir