title: High-throughput screening uncovers a compound that activates latent HIV-1 and acts cooperatively with a histone deacetylase (HDAC) inhibitor.
abstract: Current antiretroviral therapy (ART) provides potent suppression of HIV-1 replication. However, ART does not target latent viral reservoirs, so persistent infection remains a challenge. Small molecules with pharmacological properties that allow them to reach and activate viral reservoirs could potentially be utilized to eliminate the latent arm of the infection when used in combination with ART. Here we describe a cell-based system modeling HIV-1 latency that was utilized in a high-throughput screen to identify small molecule antagonists of HIV-1 latency. A more detailed analysis is provided for one of the hit compounds, antiviral 6 (AV6), which required nuclear factor of activated T cells for early mRNA expression while exhibiting RNA-stabilizing activity. It was found that AV6 reproducibly activated latent provirus from different lymphocyte-based clonal cell lines as well as from latently infected primary resting CD4(+) T cells without causing general T cell proliferation or activation. Moreover, AV6 complemented the latency antagonist activity of a previously described histone deacetylase (HDAC) inhibitor. This is a proof of concept showing that a high-throughput screen employing a cell-based model of HIV-1 latency can be utilized to identify new classes of compounds that can be used in concert with other persistent antagonists with the aim of viral clearance.
authors.affiliation: Department of Molecular Genetics, Microbiology, and Immunology, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
authors.forename: Sofiya
authors.initials: S
authors.lastname: Micheva-Viteva
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Leonard C
authors.initials: LC
authors.lastname: Edelstein
authors.forename: Annmarie L
authors.initials: AL
authors.lastname: Pacchia
authors.forename: Hui-Ling Rose
authors.initials: HL
authors.lastname: Lee
authors.forename: Jason D
authors.initials: JD
authors.lastname: Graci
authors.forename: Jamie
authors.initials: J
authors.lastname: Breslin
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Phelan
authors.forename: Leia K
authors.initials: LK
authors.lastname: Miller
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Colacino
authors.forename: Zhengxian
authors.initials: Z
authors.lastname: Gu
authors.forename: Yacov
authors.initials: Y
authors.lastname: Ron
authors.forename: Stuart W
authors.initials: SW
authors.lastname: Peltz
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Dougherty
mesh_terms: D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology; D049109:Cell Proliferation; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005434:Flow Cytometry / Q000379:methods; D015967:Gene Expression Regulation, Viral; D016679:Genome, Viral; D015497:HIV-1 / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008213:Lymphocyte Activation; D016662:Virus Integration; D017735:Virus Latency
chemical_list: D044966:Anti-Retroviral Agents; D056572:Histone Deacetylase Inhibitors