Selective HDAC inhibition for the disruption of latent HIV-1 infection.

PLoS One
Authors
Keywords
Abstract

Selective histone deacetylase (HDAC) inhibitors have emerged as a potential anti-latency therapy for persistent human immunodeficiency virus type 1 (HIV-1) infection. We utilized a combination of small molecule inhibitors and short hairpin (sh)RNA-mediated gene knockdown strategies to delineate the key HDAC(s) to be targeted for selective induction of latent HIV-1 expression. Individual depletion of HDAC3 significantly induced expression from the HIV-1 promoter in the 2D10 latency cell line model. However, depletion of HDAC1 or -2 alone or in combination did not significantly induce HIV-1 expression. Co-depletion of HDAC2 and -3 resulted in a significant increase in expression from the HIV-1 promoter. Furthermore, concurrent knockdown of HDAC1, -2, and -3 resulted in a significant increase in expression from the HIV-1 promoter. Using small molecule HDAC inhibitors of differing selectivity to ablate the residual HDAC activity that remained after (sh)RNA depletion, the effect of depletion of HDAC3 was further enhanced. Enzymatic inhibition of HDAC3 with the selective small-molecule inhibitor BRD3308 activated HIV-1 transcription in the 2D10 cell line. Furthermore, ex vivo exposure to BRD3308 induced outgrowth of HIV-1 from resting CD4+ T cells isolated from antiretroviral-treated, aviremic HIV+ patients. Taken together these findings suggest that HDAC3 is an essential target to disrupt HIV-1 latency, and inhibition of HDAC2 may also contribute to the effort to purge and eradicate latent HIV-1 infection.

Year of Publication
2014
Journal
PLoS One
Volume
9
Issue
8
Pages
e102684
Date Published
2014
ISSN
1932-6203
URL
DOI
10.1371/journal.pone.0102684
PubMed ID
25136952
PubMed Central ID
PMC4138023
Links
Grant list
T32 AI007419 / AI / NIAID NIH HHS / United States
RR024383 / RR / NCRR NIH HHS / United States
R01 DA030156 / DA / NIDA NIH HHS / United States
DA030156 / DA / NIDA NIH HHS / United States
AI50410 / AI / NIAID NIH HHS / United States
T32AI007419 / AI / NIAID NIH HHS / United States
P30 AI050410 / AI / NIAID NIH HHS / United States