SummaryBackground-Persistent infection in resting CD4+ Tcells prevents eradication of HIV-1. Since the chromatin remodeling enzyme histone deacetylase 1 (HDAC1) maintains latency of integrated HIV, we tested the ability of the HDAC inhibitor valproic acid to deplete persistent, latent infection in resting CD4 T cells.

The expression levels of ϳ4,600 cellular RNA transcripts were assessed in CD4؉ -T-cell lines at different times after infection with human immunodeficiency virus type 1 strain BRU (HIV-1 BRU ) using DNA microarrays. We found that several classes of genes were inhibited by HIV-1 BRU infection, consistent with the G 2 arrest of HIV-1-infected cells induced by Vpr. These included genes involved in cell division and transcription, a family of DEAD-box proteins (RNA helicases), and all genes involved in translation and splicing. However, the overall level of cell activation and signaling was increased in infected cells, consistent with strong virus production. These included a subgroup of transcription factors, including EGR1 and JUN, suggesting they play a specific role in the HIV-1 life cycle. Some regulatory changes were cell line specific; however, the majority, including enzymes involved in cholesterol biosynthesis, of changes were regulated in most infected cell lines. Compendium analysis comparing gene expression profiles of our HIV-1 infection experiments to those of cells exposed to heat shock, interferon, or influenza A virus indicated that HIV-1 infection largely induced specific changes rather than simply activating stress response or cytokine response pathways. Thus, microarray analysis confirmed several known HIV-1 host cell interactions and permitted identification of specific cellular pathways not previously implicated in HIV-1 infection. Continuing analyses are expected to suggest strategies for impacting HIV-1 replication in vivo by targeting these pathways.

With advances in antiretroviral therapy, HIV infection might be cleared by intensive time-limited treatment coupled with practical strategies that disrupt latency without enhancing new infection. HDAC inhibitors are capable of inducing expression of quiescent provirus, without fully activating cells or enhancing de novo infection, and may be useful in future clinical protocols that seek to eradicate HIV infection.

The objective of this study was to functionally assess gamma/delta (␥␦) T cells following pathogenic human immunodeficiency virus (HIV) infection of humans and nonpathogenic simian immunodeficiency virus (SIV) infection of sooty mangabeys. ␥␦ T cells were obtained from peripheral blood samples from patients and sooty mangabeys that exhibited either a CD4-healthy (>200 CD4 ؉ T cells/l blood) or CD4-low (<200 CD4 cells/l blood) phenotype. Cytokine flow cytometry was utilized to assess production of Th1 cytokines tumor necrosis factor alpha and gamma interferon following ex vivo stimulation with either phorbol myristate acetate/ ionomycin or the V␦2 ␥␦ T-cell receptor agonist isopentenyl pyrophosphate. Sooty mangabeys were observed to have higher percentages of ␥␦ T cells in their peripheral blood than humans did. Following stimulation, ␥␦

Finally, HMBA interferes with cell proliferation and activation; it suppressed expression of Ki67 and CD25 and in PBMCs exposed to mitogen. As HMBA has been tested in oncology trials, its unusual properties make it a useful reagent for future studies of HIV promoter regulation and a novel prototype molecule for therapeutics that abort the latent proviral state of chronic HIV infection.