Basic Science Award

Human immunodeficiency virus-1 (HIV-1), the causative agent of AIDS, remains a global health crisis with millions of new infections each year. HIV-1 hijacks diverse host factor regulatory networks in order to replicate, yet the precise components of these networks and the relationships among these host factors remain poorly characterized. HIV-1 Rev is an essential HIV-1 gene that regulates the export of HIV-1 transcripts. While putative Rev host factors have been described in the literature, few have been definitively linked to Rev function during HIV-1 infection. By employing a Rev-independent clone of HIV-1, I have recently uncovered a panel of genetically defined Rev host factors; however, it is not yet known how these host factors contribute to Rev function or how they functionally relate to each other during the context of HIV-1 infection. I propose a quantitative genetic interaction (GI) strategy to dissect the host regulatory network of bona fide HIV-1 Rev host factors. I will harness high content fluorescence microscopy and Epistatic MiniArray Profile (E-MAP) technology to quantitatively measure GIs arising during HIV-1 infection. Comparing GI profiles from an E-MAP organizes genes based on function and identifies network relationships in an unbiased fashion. Careful inspection of GI profile clusters will guide hypothesis generation for determining the precise function of Rev factors during HIV-1 infection by utilizing a breadth of experimental tools such as microscopy, molecular virology, and proteomics. A quantitative understanding of how cellular networks are hijacked by HIV-1 will expand our knowledge of basic host cell processes and identify attractive targets for anti-HIV-1 therapeutics.