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 κB enhancer elements of the HIV long terminal repeat (LTR) in the maintenance of viral latency. We show that NF‐κB 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.

Evolution of receptor specificity by viruses has several implications for viral pathogenesis, host range, virus-mediated gene targeting, and viral adaptation after organ transplantation and xenotransplantation, as well as for the emergence of viral diseases. Recent evidence suggests that minimal changes in viral genomes may trigger a shift in receptor usage for virus entry, even into the same cell type. A capacity to exploit alternative entry pathways may reflect the ancient evolutionary origins of viruses and a possible role as agents of horizontal gene transfers among cells.

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