NF-kappaB p50 promotes HIV latency through HDAC recruitment and repression of transcriptional initiation.
Cells latently infected with HIV represent a currently insurmountable barrier to viral eradication in infected patients. Using the J-Lat human T-cell model of HIV latency, we have investigated the role of host factor binding to the kappaB enhancer elements of the HIV long terminal repeat (LTR) in the maintenance of viral latency. We show that NF-kappaB p50-HDAC1 complexes constitutively bind the latent HIV LTR and induce histone deacetylation and repressive changes in chromatin structure of the HIV LTR, changes that impair recruitment of RNA polymerase II and transcriptional initiation. Knockdown of p50 expression with specific small hairpin RNAs reduces HDAC1 binding to the latent HIV LTR and induces RNA polymerase II recruitment. Similarly, inhibition of histone deacetylase (HDAC) activity with trichostatin A promotes binding of RNA polymerase II to the latent HIV LTR. This bound polymerase complex, however, remains non-processive, generating only short viral transcripts. Synthesis of full-length viral transcripts can be rescued under these conditions by expression of Tat. The combination of HDAC inhibitors and Tat merits consideration as a new strategy for purging latent HIV proviruses from their cellular reservoirs.
Williams
Samuel A
SA
Gladstone Institute of Virology and Immunology, University of California, San Francisco, CA 94158, USA.
Chen
Lin-Feng
LF
Kwon
Hakju
H
Ruiz-Jarabo
Carmen M
CM
Verdin
Eric
E
Greene
Warner C
WC
D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics; D015696:Gene Products, tat / Q000378:metabolism; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology; D016325:HIV Long Terminal Repeat / Q000235:genetics; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012319:RNA Polymerase II / Q000378:metabolism; D013601:T-Lymphocytes / Q000821:virology; D014158:Transcription, Genetic; D017735:Virus Latency / Q000235:genetics*; D054322:tat Gene Products, Human Immunodeficiency Virus
D002843:Chromatin; D015696:Gene Products, tat; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D052002:NF-kappa B p50 Subunit; D054322:tat Gene Products, Human Immunodeficiency Virus; C012589:trichostatin A; D012319:RNA Polymerase II; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases