title: Reactivation of latent HIV-1 by inhibition of BRD4.
abstract: HIV-1 depends on many host factors for propagation. Other host factors, however, antagonize HIV-1 and may have profound effects on viral activation. Curing HIV-1 requires the reduction of latent viral reservoirs that remain in the face of antiretroviral therapy. Using orthologous genetic screens, we identified bromodomain containing 4 (BRD4) as a negative regulator of HIV-1 replication. Antagonism of BRD4, via RNA interference or with a small molecule inhibitor, JQ1, both increased proviral transcriptional elongation and alleviated HIV-1 latency in cell-line models. In multiple instances, JQ1, when used in combination with the NF-κB activators Prostratin or PHA, enhanced the in vitro reactivation of latent HIV-1 in primary T cells. These data are consistent with a model wherein BRD4 competes with the virus for HIV-1 dependency factors (HDFs) and suggests that combinatorial therapies that activate HDFs and antagonize HIV-1 competitive factors may be useful for curing HIV-1 infection.
authors.affiliation: Department of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02127, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhu
authors.forename: Gaurav D
authors.initials: GD
authors.lastname: Gaiha
authors.forename: Sinu P
authors.initials: SP
authors.lastname: John
authors.forename: Thomas
authors.initials: T
authors.lastname: Pertel
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Chin
authors.forename: Geng
authors.initials: G
authors.lastname: Gao
authors.forename: Hongjing
authors.initials: H
authors.lastname: Qu
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Elledge
authors.forename: Abraham L
authors.initials: AL
authors.lastname: Brass
mesh_terms: D001381:Azepines / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D015870:Gene Expression; D057809:HEK293 Cells; D015497:HIV-1 / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010703:Phorbol Esters / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology; D014775:Virus Activation / Q000187:drug effects; D017735:Virus Latency / Q000187:drug effects; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D010703:Phorbol Esters; D034741:RNA, Small Interfering; D014157:Transcription Factors; D014230:Triazoles; D054322:tat Gene Products, Human Immunodeficiency Virus; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C070999:prostratin