Grant: Operating Grant: Innovative Biomedical and Clinical HIV/AIDS Research

Although antiretroviral therapy (ART) transformed HIV-1 infection into a manageable chronic disease, HIV remains a major health problem, with more than 36 million infected people worldwide and 2 million new infections in 2014. In Canada, new infections continue to occur among young men having sex with men, as well as within the First Nations communities. ART fails to eradicate HIV and immunological alterations persist at mucosal sites thus causing non-AIDS co-morbidities that represent a burden for the health system. T helper 17 (Th17) cells are a subset of CD4+ T-cells that play a critical role in the immunity against pathogens at intestinal surfaces. Th17 cells are depleted and their frequency/function is not restored with ART. Our group performed pioneering work demonstrating that Th17 cells are preferentially infected during mucosal transmission and that a fraction of Th17 cells is long-lived and contributes to HIV reservoir persistence during ART. Th17 cells express drug efflux pumps that may render the intracellular concentrations of ART suboptimal, thus justifying the need for additional drugs to control HIV replication in these cells. This project builds on original preliminary results demonstrating that HIV replication in Th17 cells can be counteracted by inhibitors of mammalian target of rapamycin (mTOR), an important regulator of cellular metabolism. Our goals are i) to identify molecular mechanisms by which mTOR regulates HIV replication in Th17 cells and ii) to monitor the effects of the mTOR inhibitor metformin, administered in HIV-infected individuals in the context of an approved clinical trial, on HIV reservoir reduction and intestinal mucosal immunity restoration. Of note, mTOR inhibitors are successfully used in clinics for diabetes and cancer but not yet for HIV. Together our team of experts in immunology, virology, and clinical interventions will provide the first proof-of concept that mTOR inhibitors can be used for HIV remission.