Role of cellular Helicases and Nucleases in HIV-1 infection and lentiviral transduction.

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HIV-1 needs to perform reverse transcription (RT) to convert its single-stranded (ss) RNA genome into linear double-stranded (ds) DNA prior to integration into the host cell genome. Recent studies have shown that HIV-1 capsids may remain intact until they reach or pass the nuclear pores thereby shielding RT intermediates from degradation and innate immune sensing. Prior to integration, however, the viral dsDNA must leave its protective shell. Our results suggest that this provides a window of opportunity for cellular helicase and nucleases to degrade the final RT product and to block HIV-1 just before it becomes irreversibly integrated into the cellular genome. Thus, restriction of proviral integration may directly limit the size of the latent HIV-1 reservoirs as well as the efficiency of lentiviral gene delivery. In the proposed project, we will determine the impact of BLM, EXO1, DNA2 as well as other cellular helicases and nuclease on HIV-1 infection and innate immune activation in primary CD4+ T cells and macrophages. In addition, viral mechanisms of helicase/nuclease evasion or counteraction will be investigated. Finally, we will determine whether DNA repair factors affect the efficiency of lentiviral gene delivery and the resulting levels of undesired innate immune activation. Our findings will provide new opportunities to reduce harmful chronic immune activation and the size of latent viral reservoirs in HIV-1-infected individuals, and may help to improve the efficiency and safety of lentiviral gene transfer.