Modulation of mTOR signaling using metformin during therapeutic SIV vaccination to achieve stringent post-treatment control
Most HIV-infected patients who stop taking antiretroviral drugs experience rapid viral rebound and suffer in the longer term from the presence of more virus in blood and lower CD4+ T cell counts. HIV-1 infection generally increases T-cell metabolism, which means that cells are more active, which promotes successful viral integration and replication. Our preliminary data show that although therapeutic T cell vaccination can effectively generate cytotoxic T cells that kill HIV-infected cells, in most cases this antiviral activity is insufficient to limit viral replication. It is critical to improve upon these promising vaccine strategies and to design novel approaches to target host factors to restrict virus replication and enhance vaccine-induced immunity. Metformin, one of the most widely used drugs for type II diabetes, has immuno-metabolic regulatory properties that can have beneficial effects attenuating inflammation and residual HIV transcription and enhancing vaccine-induced virus-specific memory T cells via mechanisms involving a reduction in mTOR phosphorylation/activation. We hypothesized that stringent post-treatment control requires both effective anti-SIV responses to a therapeutic vaccine and unfavorable metabolic conditions for viral replication. Here we propose to modulate the mTOR pathway to reduce T-cell activation and residual HIV transcription and to enhance the generation of T cells enriched for a stem cell memory (TSCM) phenotype in response to Ad26/gag vaccination. To achieve our goal, we will investigate two important effects of metformin in rhesus macaques; 1) its effect in controlling immune inflammation and activation and 2) its ability to create effective T-cell responses in recipients of therapeutic vaccination.