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.
Highlights
The persistence of latent human immunodeficiency virus type 1 (HIV-1) infection, despite highly effective antiretroviral therapy (ART), poses a formidable obstacle to eradication of HIV-1
The 2D10 cell line was clonally selected for a low level of basal HIV-1 expression, but it is inducible by exposure to appropriate stimuli, such as tumor necrosis factor alpha (TNF-a) or histone deacetylase (HDAC) inhibitors [27]
In an effort to determine the minimal HDAC-isoform(s) inhibition that is necessary for optimal induction of latent HIV-1, we employed an shRNA-mediated strategy to similar to depletion of HDAC3 alone, a significant increase in the percent of cells expressing GFP was observed when Mrk 12 was added to cells depleted of HDAC3
Summary
The persistence of latent human immunodeficiency virus type 1 (HIV-1) infection, despite highly effective antiretroviral therapy (ART), poses a formidable obstacle to eradication of HIV-1. This reservoir of quiescent HIV-1 proviruses is established early during acute infection and persists in long-lived resting CD4+ T cells throughout the life of an infected individual [1,2,3]. Once an HIV-1 provirus has integrated into the host’s genome, the virus can enter a quiescent state that is able to persist in the presence of ART. Replication-competent virus can be recovered from latently infected CD4+ T cells following mitogen stimulation or exposure to agents such as HDAC inhibitors or protein kinase agonists [11,12]
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