Grant: Ca. Gr.: Biomedical Res. for HIV/AIDS/STBBI -Next-gen. therapeutic interventions

The antiretroviral therapy (ART) efficiently controls viral replication to undetectable plasma levels and robustly reduces the risk of transmission (U=U, Undetectable = Untransmittable) thus, transforming the deadly HIV-1 epidemic into a manageable chronic disease. Nevertheless, ART does not cure HIV-1 and residual viral replication occurs during ART. This fuels the epidemic that remains highly active even in high income countries, such as Canada and USA. Also, people living with HIV (PLWH) are at increased risk for accelerated aging and comorbidities, thus representing a heavy burden for the health system. The major barrier to HIV-1 cure is the persistence of viral reservoirs (VRs) in long-lived immune cells, such as CD4+ T lymphocytes. These VRs are silent and undetectable by the immune system for clearance. In previous studies, our group demonstrated the beneficial effects of metformin, a drug used to treat type 2 diabetes, now repurposed as an adjuvant in cancer therapy, which reduced systemic inflammation and residual HIV transcription in ART-treated PLWH (LILAC pilot non-randomized clinical trial; NCT02659306). Most recently our group demonstrated the peculiar effects of metformin on VR reactivation, with a limited release of infectious virions that contrasted with increased expression of viral proteins inside the cells and an efficient recognition of VRs by anti-HIV-1 Envelope (Env) broadly neutralizing antibodies (bNAbs). Current trends in HIV-1 cure interventions consider the importance of combining multiple strategies for synergistic action. The complementary expertise of the co-applicants in cellular and molecular Immunology/Virology, HIV transcription, pre-clinical HIV models, and clinical HIV care, ensure the feasibility of the proposed studies, which have the potential to provide a pre-clinical proof-of-concept that metformin can be used in combination with Env bNAbs for accelerating VR decay during ART and delaying viral rebound upon ART interruption.