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 EstesJoseph Hesselgesser, Romas Geleziunas, Jeffrey D. Lifson

Research output: Contribution to journalArticle

19 Citations (Scopus)

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 1 2016

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Simian Immunodeficiency Virus
Macaca mulatta
Viral Load
HIV
Histone Deacetylase Inhibitors
Therapeutics
Viruses
romidepsin
Viremia
Viral RNA
Macaca
Combination Drug Therapy
Intravenous Infusions
Histones
Antiviral Agents

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

Elevated Plasma Viral Loads in Romidepsin-Treated Simian Immunodeficiency Virus-Infected Rhesus Macaques on Suppressive Combination Antiretroviral Therapy. / Del Prete, Gregory Q.; Oswald, Kelli; Lara, Abigail; Shoemaker, Rebecca; Smedley, Jeremy; MacAllister, Rhonda; Coalter, Vicky; Wiles, Adam; Wiles, Rodney; Li, Yuan; Fast, Randy; Kiser, Rebecca; Lu, Bing; Zheng, Jim; Alvord, W. Gregory; Trubey, Charles M.; Piatak, Michael; Deleage, Claire; Keele, Brandon F.; Estes, Jacob; Hesselgesser, Joseph; Geleziunas, Romas; Lifson, Jeffrey D.

In: Antimicrobial Agents and Chemotherapy, Vol. 60, No. 3, 01.03.2016, p. 1560-1572.

Research output: Contribution to journalArticle

Del Prete, GQ, 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, WG, Trubey, CM, Piatak, M, Deleage, C, Keele, BF, Estes, J, Hesselgesser, J, Geleziunas, R & Lifson, JD 2016, 'Elevated Plasma Viral Loads in Romidepsin-Treated Simian Immunodeficiency Virus-Infected Rhesus Macaques on Suppressive Combination Antiretroviral Therapy', Antimicrobial Agents and Chemotherapy, vol. 60, no. 3, pp. 1560-1572. https://doi.org/10.1128/AAC.02625-15
Del Prete, Gregory Q. ; Oswald, Kelli ; Lara, Abigail ; Shoemaker, Rebecca ; Smedley, Jeremy ; MacAllister, Rhonda ; Coalter, Vicky ; Wiles, Adam ; Wiles, Rodney ; Li, Yuan ; Fast, Randy ; Kiser, Rebecca ; Lu, Bing ; Zheng, Jim ; Alvord, W. Gregory ; Trubey, Charles M. ; Piatak, Michael ; Deleage, Claire ; Keele, Brandon F. ; Estes, Jacob ; Hesselgesser, Joseph ; Geleziunas, Romas ; Lifson, Jeffrey D. / Elevated Plasma Viral Loads in Romidepsin-Treated Simian Immunodeficiency Virus-Infected Rhesus Macaques on Suppressive Combination Antiretroviral Therapy. In: Antimicrobial Agents and Chemotherapy. 2016 ; Vol. 60, No. 3. pp. 1560-1572.
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AU - Lara, Abigail

AU - Shoemaker, Rebecca

AU - Smedley, Jeremy

AU - MacAllister, Rhonda

AU - Coalter, Vicky

AU - Wiles, Adam

AU - Wiles, Rodney

AU - Li, Yuan

AU - Fast, Randy

AU - Kiser, Rebecca

AU - Lu, Bing

AU - Zheng, Jim

AU - Alvord, W. Gregory

AU - Trubey, Charles M.

AU - Piatak, Michael

AU - Deleage, Claire

AU - Keele, Brandon F.

AU - Estes, Jacob

AU - Hesselgesser, Joseph

AU - Geleziunas, Romas

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