Effects of Treatment with Suppressive Combination Antiretroviral Drug Therapy and the Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid; (SAHA) on SIV-Infected Chinese Rhesus Macaques

Abstract

ObjectivesViral reservoirs–persistent residual virus despite combination antiretroviral therapy (cART)–remain an obstacle to cure of HIV-1 infection. Difficulty studying reservoirs in patients underscores the need for animal models that mimics HIV infected humans on cART. We studied SIV-infected Chinese-origin rhesus macaques (Ch-RM) treated with intensive combination antiretroviral therapy (cART) and 3 weeks of treatment with the histone deacetyalse inhibitor, suberoylanilide hydroxamic acid (SAHA).MethodsSIVmac251 infected Ch-RM received reverse transcriptase inhibitors PMPA and FTC and integrase inhibitor L-870812 beginning 7 weeks post infection. Integrase inhibitor L-900564 and boosted protease inhibitor treatment with Darunavir and Ritonavir were added later. cART was continued for 45 weeks, with daily SAHA administered for the last 3 weeks, followed by euthanasia/necropsy. Plasma viral RNA and cell/tissue-associated SIV gag RNA and DNA were quantified by qRT-PCR/qPCR, with flow cytometry monitoring changes in immune cell populations.ResultsUpon cART initiation, plasma viremia declined, remaining <30 SIV RNA copy Eq/ml during cART, with occasional blips. Decreased viral replication was associated with decreased immune activation and partial restoration of intestinal CD4+ T cells. SAHA was well tolerated but did not result in demonstrable treatment-associated changes in plasma or cell associated viral parameters.ConclusionsThe ability to achieve and sustain virological suppression makes cART-suppressed, SIV-infected Ch-RM a potentially useful model to evaluate interventions targeting residual virus. However, despite intensive cART over one year, persistent viral DNA and RNA remained in tissues of all three animals. While well tolerated, three weeks of SAHA treatment did not demonstrably impact viral RNA levels in plasma or tissues; perhaps reflecting dosing, sampling and assay limitations.

Reactivation of simian immunodeficiency virus reservoirs in the brain of virally suppressed macaques

“…Again, no changes in viral load were observed and ingenol-B treatment was withdrawn for 2 weeks. Treatment was reinitiated and maintained for 10 days at 1 mg/kg per day in combination with the HDAC inhibitor vorinostat (6 mg/kg subcutaneous infusion four times), which is known to synergize with PKC agonists and does not appear to successfully impact viral reservoirs as monotherapy [18,37]. Animals were kept on CNS-penetrant ART until the end of the experiment and suppressive levels of antiretroviral drugs were detected in blood, brain, spleen, and liver of all three macaques (Table S3).…”

Animal models to achieve an HIV cure

“…Agents designed to reactivate latent virus (latency reversing agents, LRA), including histone de-acetylase inhibitors (HDACi) such as Vorinostat, Panobinastat, and Romidepsin, and a drug used to treat alcohol addiction Disulfiram, have been used safely in HIV-infected individuals in several pilot studies, although with limited impact on virus reactivation and virtually no effect on the size of the virus reservoirs (67–71). Ling et al and Del Prete et al tested Vorinostat in suppressed SIV infection of Chinese and Indian RM, respectively, and obtained results similar to those of the above mentioned human clinical trials (72,73). Del Prete et al have also recently used a pan HDACi, Romidepsin, to reactivate SIV infection in ART-treated RMs (74).…”

Animal Models for HIV Cure Research

“… a Haase ( 56 ), Lackner and Veazey ( 57 ), Demberg et al ( 58 ), Horiike et al ( 59 ), Pandrea et al ( 60 ), Ma et al ( 61 ), Uberla et al ( 62 ), North et al ( 12 ), North et al ( 63 ), Kauffman et al ( 64 ), Monceaux et al ( 65 ), Ling et al ( 66 ), Ling et al ( 67 ), Klatt et al ( 68 ), Dinoso et al ( 27 ), Canary et al ( 69 ), Hirsch et al ( 70 ), Mandell et al ( 71 ), Kristoff et al ( 72 ), Ambrose et al ( 73 ), Shao et al ( 74 ), Kearney et al ( 75 ), Kline et al ( 13 ), Benlhassan-Chahour et al ( 76 ), Mannioui et al ( 77 ), Sellier et al ( 78 ), Reimann et al ( 79 ), and Budde et al ( 80 ) . …”

“…SIVmac239/251-infected Chinese RMs represents another model of interest for cure research. Compared to Indian RMs, Chinese RMs have lower acute and chronic VLs, more closer to HIV-1 infected humans, and as such, SIV infection can be more readily controlled in Chinese RMs than in Indian RMs ( 67 , 108 ).…”

“…The virally suppressed SIV/RM models have allowed the testing of several latency reversal agents (LRAs) to determine their ability to reactivate latent virus and assess the impact of this strategy on the size of the overall reservoir. Administration of the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) to SIV-infected ART-suppressed RMs induced a very limited amount of virus reactivation, in spite of inducing a discernable increase in histone acetylation, indicating that repeated HDACi administrations may be necessary to see a more robust effect ( 67 , 124 ). The NHP model can further be employed to test various hypotheses based on ex vivo experiments using HDACi.…”