Grant: Team Grant: HIV/AIDS Biomedical and Clinical Research - Cure - Large

Despite the success of antiretroviral therapy (ART) in decreasing mortality for HIV-infected individuals, ART has not cured HIV/AIDS. The failure to eradicate HIV infection during ART stems from the virus' ability to persist in the body in multiple cell types and tissues. Without lifetime therapy, the virus quickly rebounds resulting in accelerated morbidity and mortality. The most commonly studied form of persistence is in memory CD4+ T-cells (CD4+ Tm-cells) that are harboring virus out of view of drugs or from the immune system. However, evidence indicates that other long-lived cells, known as myeloid cells, might contribute to HIV persistence. Cells that allow virus persistence are called viral reservoirs (VRs) and represent the main barrier to an HIV cure. While much is known about HIV persistence, many puzzles remain about the source of persistent HIV, the mechanisms underlying the establishment and persistence of VRs, particularly in CD4+ Tm-cells, and the ways to eliminate VRs. The Canadian HIV Cure Enterprise 2.0 (CanCURE 2.0), a team of leading Canadian HIV researchers, proposes an integrated and innovative research program informed by new knowledge in the field and new findings generated under CanCURE 1.0 (2014-2019) to: 1) Define the role and impact of long-lived self-renewing tissue-resident myeloid cells called macrophages in HIV persistence during ART; 2) Conduct detailed mechanistic studies aimed at understanding the critical role played by myeloid cells in the establishment and persistence of VR in CD4+ Tm-cells; 3) Identify new therapeutic strategies to tackle HIV persistence that capitalize on these discoveries and pursue the preclinical and clinical development of therapeutic interventions aimed at targeting VRs initiated under CanCURE 1.0. These studies are all aimed at finding new effective approaches to curing HIV infection in humans by eliminating persistent HIV infection from VRs in ART-treated patients.