Abstract
To date, a series of histone deacetylases have been documented to restrict HIV-1 replication at different steps. In this study, we identified histone deacetylase 10 (HDAC10) as an inhibitory factor against HIV-1 replication. Our results showed that endogenous HDAC10 is downregulated at the transcriptional level during HIV-1 replication. By knocking down HDAC10 in CD4+ T cells with specific shRNAs, we observed that the downregulation of HDAC10 significantly facilitates viral replication. Moreover, RQ-PCR analysis revealed that the downregulation of HDAC10 increased viral integrated DNA. Further, we identified that HDAC10 interacts with the HIV-1 integrase (IN) and that the region of residues from 55 to 165 in the catalytic domain of IN is required for HDAC10 binding. Interestingly, we found that the interaction between HDAC10 and IN specifically decreases the interaction between IN and cellular protein lens epithelium-derived growth factor (LEDGF/p75), which consequently leads to the inhibition of viral integration. In addition, we have investigated the role of HDAC10 in the late stage of viral replication by detecting the infectiousness of progeny virus produced from HDAC10 knockdown cells or HDAC10 overexpressing cells and revealed that the progeny virus infectivity is increased in the HDAC10 downregulated cells, but decreased in the HDAC10 overexpressed cells. Overall, these findings provide evidence that HDAC10 acts as a cellular inhibitory factor at the early and late stages of HIV-1 replication.
Highlights
Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl groups from lysine residues in histones and various non-histone proteins
Previous studies have identified a series of HDACs and characterized their roles in HIV-1 replication, our understanding of the influence of HDACs on HIV-1 replication is still limited
We identified histone deacetylase 10 (HDAC10) as an HIV-1 inhibitory factor and studied its inhibitory function during HIV-1 replication
Summary
Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl groups from lysine residues in histones and various non-histone proteins. HDACs are involved in the inhibition of gene expression and a series of HDAC family members have been reported to act as inhibitory factors against HIV-1 infection [1]. HDAC1 and HDAC2 induce the deacetylation of histone H3 and H4 to regulate the degree of compaction of chromatin, which inhibits viral transcription and subsequently contributes to the formation of HIV-1 latency [2]. HDAC6 has been reported to inhibit HIV-mediated target cell fusion and entry by preventing the acetylation of cortical tubulin and reduce progeny virus infectiousness by preventing Vif-mediated A3G degradation [3,4]. Our studies revealed that another member of the HDAC family, Histone Deacetylases 10. HDAC10 consists of 669 amino acid residues with a bipartite modular structure, which comprises an N-terminal
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