mTOR Overcomes Multiple Metabolic Restrictions to Enable HIV-1 Reverse Transcription and Intracellular Transport

Cellular metabolism governs the susceptibility of CD4 T cells to HIV-1 infection. Multiple early post-fusion steps of HIV-1 replication are restricted in resting peripheral blood CD4 T cells; however, molecular mechanisms that underlie metabolic control of these steps remain undefined. Here, we show that mTOR activity following T cell stimulatory signals overcomes metabolic restrictions in these cells by enabling the expansion of dNTPs to fuel HIV-1 reverse transcription (RT), as well as increasing acetyl-CoA to stabilize microtubules that transport RT products. We find that catalytic mTOR inhibition diminishes the expansion of pools of both of these metabolites by limiting glucose and glutamine utilization in several pathways, thereby suppressing HIV-1 infection. We demonstrate how mTOR-coordinated biosyntheses enable the early steps of HIV-1 replication, add metabolic mechanisms by which mTOR inhibitors block HIV-1, and identify some metabolic modules downstream of mTOR as druggable targets for HIV-1 inhibition. [Display omitted] •mTOR activity controls the susceptibility of CD4 T cells to HIV-1 infection•mTOR signaling coordinates anabolic activities for dNTP synthesis that fuel HIV RT•mTOR induces stabilization of microtubules co-opted for cytoplasmic transport of HIV-1•Catalytic mTOR inhibitors potently suppress HIV-1 infection Taylor et al. show that mTOR links cellular metabolism to the susceptibility of CD4 T cells to HIV-1 infection by expanding the pools of metabolites that facilitate the synthesis of reverse transcription products and their cytoplasmic transport toward the nucleus. They also characterize targets for HIV-1 interventions downstream of mTOR signaling.