title: Elevated Plasma Viral Loads in Romidepsin-Treated Simian Immunodeficiency Virus-Infected Rhesus Macaques on Suppressive Combination Antiretroviral Therapy.
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 (n = 5) or saline (n = 3) starting 31 to 54 weeks after cART initiation. In vivo RMD treatment resulted in significant transient increases in acetylated histone levels in CD4(+) T 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.
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Gregory Q
authors.initials: GQ
authors.lastname: Del Prete
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Kelli
authors.initials: K
authors.lastname: Oswald
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Abigail
authors.initials: A
authors.lastname: Lara
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Shoemaker
authors.affiliation: Laboratory Animal Sciences Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Smedley
authors.affiliation: Laboratory Animal Sciences Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Rhonda
authors.initials: R
authors.lastname: Macallister
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Vicky
authors.initials: V
authors.lastname: Coalter
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Wiles
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Rodney
authors.initials: R
authors.lastname: Wiles
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Randy
authors.initials: R
authors.lastname: Fast
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Kiser
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Lu
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Jim
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Statistical Consulting, Data Management Services, Inc., Frederick, Maryland, USA.
authors.forename: W Gregory
authors.initials: WG
authors.lastname: Alvord
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Trubey
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Piatak
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Claire
authors.initials: C
authors.lastname: Deleage
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Brandon F
authors.initials: BF
authors.lastname: Keele
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Estes
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Hesselgesser
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Romas
authors.initials: R
authors.lastname: Geleziunas
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA lifsonj@mail.nih.gov.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lifson
mesh_terms: D000107:Acetylation; D000818:Animals; D023241:Antiretroviral Therapy, Highly Active; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D047630:Depsipeptides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D056572:Histone Deacetylase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006657:Histones / Q000378:metabolism; D008253:Macaca mulatta / Q000821:virology*; D012367:RNA, Viral / Q000097:blood*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D015302:Simian Immunodeficiency Virus / Q000187:drug effects*; D019562:Viral Load / Q000187:drug effects*; D014766:Viremia / Q000188:drug therapy; D014775:Virus Activation / Q000187:drug effects
chemical_list: D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D012367:RNA, Viral; C087123:romidepsin