Elevated Plasma Viral Loads in Romidepsin-Treated Simian Immunodeficiency Virus-Infected Rhesus Macaques on Suppressive Combination Antiretroviral Therapy

Gregory Q. Del Prete, Kelli Oswald, Abigail Lara, Rebecca Shoemaker, Jeremy Smedley, Rhonda Macallister, Vicky Coalter, Adam Wiles, Rodney Wiles, Yuan Li, Randy Fast, Rebecca Kiser, Bing Lu, Jim Zheng, W. Gregory Alvord, Charles M. Trubey, Michael Piatak, Claire Deleage, Brandon F. Keele, Jacob D. EstesJoseph Hesselgesser, Romas Geleziunas, Jeffrey D. Lifson

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Replication-competent human immunodeficiency virus (HIV) persists in infected people despite suppressive combination antiretroviral therapy (cART), and it represents a major obstacle to HIV functional cure or eradication. We have developed a model of cART-mediated viral suppression in simian human immunodeficiency virus (SIV) mac239-infected Indian rhesus macaques and evaluated the impact of the histone deacetylase inhibitor (HDACi) romidepsin (RMD) on viremia in vivo. Eight macaques virologically suppressed to clinically relevant levels (>30 viral RNA copies/ml of plasma), using a three-class five-drug cART regimen, received multiple intravenous infusions of either RMD (n5) or saline (n3) starting 31 to 54 weeks after cART initiation. In vivo RMD treatment resulted in significant transient increases in acetylated histone levels in CD4T cells. RMD-treated animals demonstrated plasma viral load measurements for each 2-week treatment cycle that were significantly higher than those in saline control-treated animals during periods of treatment, suggestive of RMD-induced viral reactivation. However, plasma virus rebound was indistinguishable between RMD-treated and control-treated animals for a subset of animals released from cART. These findings suggest that HDACi drugs, such as RMD, can reactivate residual virus in the presence of suppressive antiviral therapy and may be a valuable component of a comprehensive HIV functional cure/eradication strategy.

Original languageEnglish (US)
Pages (from-to)1560-1572
Number of pages13
JournalAntimicrobial agents and chemotherapy
Volume60
Issue number3
DOIs
StatePublished - Mar 2016

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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    Del Prete, G. Q., Oswald, K., Lara, A., Shoemaker, R., Smedley, J., Macallister, R., Coalter, V., Wiles, A., Wiles, R., Li, Y., Fast, R., Kiser, R., Lu, B., Zheng, J., Alvord, W. G., Trubey, C. M., Piatak, M., Deleage, C., Keele, B. F., ... Lifson, J. D. (2016). Elevated Plasma Viral Loads in Romidepsin-Treated Simian Immunodeficiency Virus-Infected Rhesus Macaques on Suppressive Combination Antiretroviral Therapy. Antimicrobial agents and chemotherapy, 60(3), 1560-1572. https://doi.org/10.1128/AAC.02625-15