Identification of Novel Compounds That Inhibit HIV-1 Gene Expression by Targeting Viral RNA Processing

Novel strategies targeting different stages of the HIV lifecycle are vital for continued success in combating viral infection. Since HIV gene expression is dependent upon controlled splicing of the viral transcript, small molecule modulators of RNA processing hold tremendous promise as novel drugs. To this end, we screened splicing modulators for their effect on HIV-1 gene expression. We identified four compounds, 191, 791, 833 and 892, that strongly suppressed accumulation of HIV-1 incompletely spliced RNA and expression of viral structural/regulatory proteins. Furthermore, compound treatment had limited effects on alternative splicing of host RNA splicing events. Subsequent studies confirmed anti-HIV activity of two compounds in the context of peripheral blood mononuclear cells. The distinct effects of these compounds from previously characterized HIV-1 RNA processing inhibitors validate targeting this stage of the virus lifecycle. Elucidating the mechanism by which these compounds alter HIV-1 gene expression holds key insights for novel therapeutic strategies.M.Sc.2016-11-20 00:00:0