Genetics and biology of drug resistant HIV . (360G-Wellcome-108082_Z_15_Z)

Early treatment of HIV as a means of prevention is seen as the major component of future strategies aimed at controlling the epidemic. South Africa hosts the largest ART cohort in the world - a unique environment to explore the wider implications of universal ART. The move to early ART will confer unprecedented selection pressure on the virus, with serious implications for subsequent lines of therapy, and HIV pathogenesis/transmission. In particular resistance to a core drug class - protease in hibitors - is poorly understood but could involve 3 genes or more genes including gag, pol and env. Given two of these are structural proteins interacting directly with the host, escaping virus could have altered cell tropism, antibody sensitivity, innate immune interactions and transmissibility both between cells and across mucosal surfaces. I propose to work between WT Africa Centre and the UCL London campus to gain insight into the pathogenic features of escaping viruses, as well as identifyi ng more precisely than ever before the determinants of protease inhibitor failure and likely efficacy of salvage therapies for patients failing these core agents. In order to achieve this, we will perform whole genome viral sequencing from patients pre and post failure, and we will also sythesize 10 pairs of full-length infectious clones representing baseline and escaping viruses. These reagents will be used to generate viruses for use within primary cell (T cell, macrophage) as well as humanize d mouse models of pathogenesis to understand potential biological implications of resistant viruses.