Abstract

MOLBA02 - Oral Abstract Session

Evaluation of treatment with the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid; SAHA) in antiretroviral drug treated, SIVmac239-infected rhesus macaques

Presented by Jeff Lifson (United States).

J. Lifson¹, G. Del Prete¹, R. Kiser¹, C.M. Trubey¹, J. Smedley², V. Coalter¹, K. Oswald¹, R. Shoemaker¹, R. Fast¹, Y. Li¹, A. Lara¹, A. Wiles¹, R. Wiles¹, R. Macallister², R. Sanchez³, J. Wai³, C. Tan³, B. Keele¹, J. Estes¹, M. Piatak, Jr.¹, D. Hazuda<sup>3

1</sup>SAIC Frederick, Inc., Frederick Naitonal Laboratory for Cancer Research, AIDS and Cancer Virus Program, Frederick, MD, United States, ²SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Laboratory Animal Sciences Program, Frederick, MD, United States, ³Merck Research Laboratories, West Point, PA, United States

Background: Nonhuman primate (NHP) models are needed for evaluation of proposed but unproven, and potentially dangerous strategies targeting residual virus and latent reservoirs in AIDS virus-infected subjects receiving suppressive antiretroviral drug treatment (ART), but such models have proven challenging to develop.
Methods: We treated a cohort of 6 Indian rhesus macaques with a novel three class (NRTI, PI, IN-STI) six drug (PMPA/FTC/DRV-RTV/L-870812/L-870564) ART regimen beginning at 4 weeks post-infection with SIVmac239. Peripheral blood CD4+ T cells from ART-treated animals with suppressed viremia were evaluated ex vivo for responses to SAHA, including changes in histone acetylation patterns and induction of expression of SIV. Beginning approximately 26 weeks post infection, animals received four 21 day courses of daily treatment with SAHA, with each course of SAHA separated by an approximately 3 week interval, with continuous ART throughout and longitudinal sampling of blood and lymph nodes for immunological, virological, and pharmacodynamic evaluations. Animals were euthanized and necropsied after the final SAHA dose, while still on ART, and tissues studied virologically.
Results: The ART regimen was feasible, safe and well tolerated over one year of treatment and allowed suppression of plasma viremia to < 30 copy Eq/mL. Ex vivo SAHA treatment of CD4+ T cells from ART-suppressed macaques increased histone acetylation and induced SIV expression. SAHA treatment of macaques was safe and well tolerated, and induced measurable in vivo changes in histone acetylation in CD4+ T cells but did not reproducibly impact plasma viremia. Analysis of cell associated viral DNA and RNA levels from blood and tissues is in progress and will be presented.
Conclusions: This study demonstrates the feasibility of developing and applying NHP models for studying AIDS virus reservoirs and eradication strategies, along with the in vivo safety of SAHA treatment at pharmacologically active doses.