MOLECULAR MECHANISMS OF UVB INDUCIBLE HIV ACTIVATION

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In vitro and transgenic animal studies have provided clear evidence that ultraviolet (UV) radiation can activate the human immunodeficiency virus (HIV). We have shown that similar activation occurs in UVB-exposed skin of HIV+ individuals. The aims of this pilot and feasibility study are: (1) to illuminate the molecular mechanisms underlying UVB-inducible HIV activation, and (2) to identify agents that can block this activation. Under the first aim, we will determine whether DNA photoproducts (thymidine dinucleotides or pTpT) can trigger HIV activation. We will also ascertain and characterize the role of the NFkappaB pathway in this process. And we will evaluate whether TNFalpha contributes to this activation. Under the second aim, we will examine effects of sunscreens, NFkappaB inhibitors (aspirin, salicylate, and IL-II) and thalidomide on UVB-, pTpT-, and TNFalpha-inducible HIV activation. Methods include a quantitative RT-PCR assay for measuring HIV-1 gag in human skin specimens; CAT assay of HIV-LTR-CAT transfected Jurkat cells and IKK kinase assays for examining the NFkappaB pathway; and ELISA, RT-PCR and Northern blotting for assessing TNFalpha protein and mRNA expression. These studies will produce an improved understanding of UVB-inducible HIV activation and yield therapeutic options for intervening in this process. It should also advance the goal of separating UV-driven pathways with adverse consequences from those with predominantly beneficial effects.