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.
Highlights
Combination antiretroviral therapy can successfully suppress HIV-1 replication in blood to below levels detectable by standard clinical assays for plasma HIV-1 RNA for prolonged periods, yet HIV-1 is typically not eliminated [1]
Viral levels in the gut-associated lymphoid tissue (GALT) are still measurable in HIV-1 patients on long-term successful ART [5] and we have shown that the large intestine can harbor much virus, even in SIVinfected animals with low or undetectable viremia [6]
In a previous study of Chinese-origin rhesus macaques (Ch-RM) infected with SIV, we showed that a different combination antiretroviral therapy (cART) regimen was able to suppress viral replication to less than 50 copy Eq/ml after 2–3 weeks of therapy, and this level of suppression was maintained for months
Summary
Combination antiretroviral therapy (cART) can successfully suppress HIV-1 replication in blood to below levels detectable by standard clinical assays for plasma HIV-1 RNA for prolonged periods, yet HIV-1 is typically not eliminated [1]. An advantage of animal models is the ability to sample tissues more extensively than is typically feasible in a clinical setting, allowing assessment of residual virus, and the effects of combination treatment strategies in compartments other than blood. Another advantage is that experimental therapies with multiple drug combinations can be employed in more radical attempts to eradicate virus from infected hosts, and conduct proof of concept testing of experimental ‘‘cure’’ strategies for which risk/benefit assessments may preclude long-term use in humans
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