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

OBJECTIVES:

Viral 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).

METHODS:

SIVmac251 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.

RESULTS:

Upon 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.

CONCLUSIONS:

The 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.

• Authors: Binhua Ling, Michael Piatak Jr, Linda Rogers, Ann-Marie Johnson, Kasi Russell-Lodrigue, Daria J Hazuda, Jeffrey D Lifson, Ronald S Veazey
• Journal: PloS one (PLoS One) Vol. 9 Issue 7 Pg. e102795 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 25033210 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Anti-Retroviral Agents
• DNA, Viral
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• L870812
• Naphthyridines
• RNA, Viral
• Sulfonamides
• Vorinostat
• Ritonavir
• Darunavir

Topics

• Animals
• Anti-Retroviral Agents (pharmacology)
• CD4-Positive T-Lymphocytes (drug effects, virology)
• DNA, Viral (drug effects)
• Darunavir
• Drug Therapy, Combination (methods)
• Female
• Histone Deacetylase Inhibitors (pharmacology)
• Hydroxamic Acids (pharmacology)
• Macaca mulatta (virology)
• Naphthyridines (pharmacology)
• RNA, Viral (drug effects)
• Ritonavir (pharmacology)
• Simian Acquired Immunodeficiency Syndrome (diet therapy, virology)
• Simian Immunodeficiency Virus (drug effects)
• Sulfonamides (pharmacology)
• Viremia (drug therapy, virology)
• Virus Replication (drug effects)
• Vorinostat