TY - JOUR
T1 - Elevated Plasma Viral Loads in Romidepsin-Treated Simian Immunodeficiency Virus-Infected Rhesus Macaques on Suppressive Combination Antiretroviral Therapy
AU - Del Prete, Gregory Q.
AU - Oswald, Kelli
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 D.
AU - Hesselgesser, Joseph
AU - Geleziunas, Romas
AU - Lifson, Jeffrey D.
N1 - Publisher Copyright:
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
PY - 2016/3
Y1 - 2016/3
N2 - 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.
AB - 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.
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U2 - 10.1128/AAC.02625-15
DO - 10.1128/AAC.02625-15
M3 - Article
C2 - 26711758
AN - SCOPUS:84960426869
SN - 0066-4804
VL - 60
SP - 1560
EP - 1572
JO - Antimicrobial agents and chemotherapy
JF - Antimicrobial agents and chemotherapy
IS - 3
ER -