Date Published: September 15, 2016
Publisher: Public Library of Science
Author(s): Benjamin B. Policicchio, Cuiling Xu, Egidio Brocca-Cofano, Kevin D. Raehtz, Tianyu He, Dongzhu Ma, Hui Li, Ranjit Sivanandham, George S. Haret-Richter, Tammy Dunsmore, Anita Trichel, John W. Mellors, Beatrice H. Hahn, George M. Shaw, Ruy M. Ribeiro, Ivona Pandrea, Cristian Apetrei, Guido Silvestri.
Viruses that persist despite seemingly effective antiretroviral treatment (ART) and can reinitiate infection if treatment is stopped preclude definitive treatment of HIV-1 infected individuals, requiring lifelong ART. Among strategies proposed for targeting these viral reservoirs, the premise of the “shock and kill” strategy is to induce expression of latent proviruses [for example with histone deacetylase inhibitors (HDACis)] resulting in elimination of the affected cells through viral cytolysis or immune clearance mechanisms. Yet, ex vivo studies reported that HDACis have variable efficacy for reactivating latent proviruses, and hinder immune functions. We developed a nonhuman primate model of post-treatment control of SIV through early and prolonged administration of ART and performed in vivo reactivation experiments in controller RMs, evaluating the ability of the HDACi romidepsin (RMD) to reactivate SIV and the impact of RMD treatment on SIV-specific T cell responses. Ten RMs were IV-infected with a SIVsmmFTq transmitted-founder infectious molecular clone. Four RMs received conventional ART for >9 months, starting from 65 days post-infection. SIVsmmFTq plasma viremia was robustly controlled to <10 SIV RNA copies/mL with ART, without viral blips. At ART cessation, initial rebound viremia to ~106 copies/mL was followed by a decline to < 10 copies/mL, suggesting effective immune control. Three post-treatment controller RMs received three doses of RMD every 35–50 days, followed by in vivo experimental depletion of CD8+ cells using monoclonal antibody M-T807R1. RMD was well-tolerated and resulted in a rapid and massive surge in T cell activation, as well as significant virus rebounds (~104 copies/ml) peaking at 5–12 days post-treatment. CD8+ cell depletion resulted in a more robust viral rebound (107 copies/ml) that was controlled upon CD8+ T cell recovery. Our results show that RMD can reactivate SIV in vivo in the setting of post-ART viral control. Comparison of the patterns of virus rebound after RMD administration and CD8+ cell depletion suggested that RMD impact on T cells is only transient and does not irreversibly alter the ability of SIV-specific T cells to control the reactivated virus.
Viral reservoirs are infected cells that persist even in the face of seemingly effective suppressive antiretroviral therapy (ART) and can give rise to recrudescent infection when ART is stopped. Reservoir cells include latently infected resting, memory CD4+ T cells, as well as other cells, such as T memory stem cells (TSCM) or T follicular helper cells (Tfh) [1–8]. Cells harboring latent proviruses carry the virus for the duration of their lifespan. As the half-life of central memory T helper cells is estimated at 44 months , and even longer for the TSCM and Tfh [6,10,11], and latently infected cells that do not express viral antigens are invisible to immune clearance mechanisms, such cells can persist for decades, even in patients successfully treated with ART [12–16]. Upon stochastic reactivation, perhaps in connection with homeostatic proliferation or antigen specific stimulation, these quiescent cells can revert their status and start producing new virions [5,17]. Even if expression of viral antigens results in immune clearance, the virus will persist as long as proliferation equals or exceeds clearance. ART may suppress most de novo infections of susceptible cells by virions derived from reactivated cells, but viral rebound occurs after variable delays at the cessation of ART, with plasma viral load (PVLs) typically rebounding to pretreatment levels [18,19]. With an estimated 1 latently infected cell per 1×106 CD4+ T cells , current paradigms predict that the latent viral reservoir is unlikely to be naturally eliminated over the lifetime of an HIV-infected individual on ART [21,22].
As research for a cure for HIV/AIDS gathers momentum, so does the use of animal models that can be employed to answer multiple key questions related to HIV infection pertinent to potential curative strategies, such as the location and structure of viral reservoirs, the impact of various therapeutic approaches on these reservoirs, as well as the toxicity of candidate LRAs . These questions cannot be addressed without very invasive sampling and without major risks that can be achieved in animal models, but not in a clinical setting where the standard of care for HIV-infected individuals on ART means that in spite of being on chronic medication, they are otherwise able to have a virtually normal life, with a life expectancy that nears that of HIV-uninfected patients .