This fellowship training program proposes rigorous didactics, innovative research, and strong inter-disciplinary collaborations aiding both. It will prepare me for productivity in translational HIV research, as my goal is an academic career as a physician-scientist advancing elimination of non-AIDS complications of ART-treated HIV infection. The research proposal builds on my sponsor's recent work on T cell metabolic reprogramming and HIV replication, extending it to monocyte-related immunopathogenesis of cardiovascular disease in HIV infected patients. My preliminary data indicate that a catalytic mTOR inhibitor (mTORi), as well as a statin, diminish ex vivo activation of downstream effectors of mTOR in monocytes from uninfected persons, and suppress emergence of inflammatory monocyte phenotypes after TLR engagement. A more complete characterization of the mTOR signaling pathway and its downstream functions in monocytes is proposed to rigorously delineate its contribution to ongoing inflammation in ART-treated HIV-1 infection.
Aim 1 will determine whether mTOR activity is necessary and sufficient for monocytes to develop an inflammatory phenotype after exposure ex vivo to LPS (a TLR4 ligand) and RNA (a defined TLR7/8 ligand). I will also determine whether the inflammatory phenotype of monocytes isolated from HIV-infected donors can be reversed by ex vivo exposure to mTORi. I also propose to extend my additional preliminary results supporting the hypothesis that inhibition of mTORC1-dependent cellular functions contributes to the anti-inflammatory effects of statins.
Aim 2 will evaluate the effect of ex vivo statin (rosuvastatin) treatment on mTORC1 and mTORC2 activity in unstimulated and TLR-stimulated monocytes from uninfected subjects, as well as whether rosuvastatin blocks a shift to inflammatory CD16+ monocyte phenotypes. I will rigorously study causality using genetic approaches to impact mTORC1, and also determine whether starting in vivo statin treatment in HIV patients with recent coronary events is associated with decreasing mTOR activity in their monocytes.
This project will provide rigorous training in molecular HIV pathogenesis research, as well as cross-disciplinary collaboration. It holds promise for new treatment strategies that block cellular metabolic reprogramming by inhibiting mTOR to diminish systemic inflammation that persists during suppressive ART and is implicated in accelerated cardiovascular disease in HIV patients.
