@article{225cee63a750444983c48928499aca4e,
title = "mTOR Overcomes Multiple Metabolic Restrictions to Enable HIV-1 Reverse Transcription and Intracellular Transport",
abstract = "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.",
keywords = "CD4 T cells, HIV-1, HIV-1 replication, host-virus interactions, immunometabolism, mTOR, mTORC1, mTORC2, microtubule stabilization, reverse transcription",
author = "Taylor, {Harry E.} and Nina Calantone and Drew Lichon and Hannah Hudson and Isabelle Clerc and Campbell, {Edward M.} and D'Aquila, {Richard T.}",
note = "Funding Information: This work was supported by NIH P01 AI 131346 , a Northwestern Medicine Catalyst Award to R.T.D., and a Developmental Core Pilot Project award to H.E.T. from the Third Coast Center for AIDS Research (CFAR), an NIH-funded center ( P30 AI117943 ). H.E.T. was also supported by start-up funds from the State of New York and the Research Foundation for SUNY . N.C. was supported by NIH F30 AI 131937 . Flow cytometry was conducted at the Northwestern UniversityFlow Cytometry Core Facility, supported by Cancer Center Support Grant NCI CA060553 . Also appreciated are Third Coast CFAR Viral Pathogenesis Core services ( P30 AI117943 ); cryopreserved cells from the biorepository of U01 DA 036939 ; the expert dNTP quantitation and consultation from Peter L. Anderson, PharmD, at the Skaggs School of Pharmacy and Pharmaceutical Sciences of the University of Colorado Anschutz Medical Campus; advice from Leonidas C. Platanias, MD, PhD; and critical review of the manuscript by members of the Northwestern HIV Translational Research Center (Chisu Song and Gael Scholtes). Funding Information: This work was supported by NIH P01 AI 131346, a Northwestern Medicine Catalyst Award to R.T.D. and a Developmental Core Pilot Project award to H.E.T. from the Third Coast Center for AIDS Research (CFAR), an NIH-funded center (P30 AI117943). H.E.T. was also supported by start-up funds from the State of New York and the Research Foundation for SUNY. N.C. was supported by NIH F30 AI 131937. Flow cytometry was conducted at the Northwestern UniversityFlow Cytometry Core Facility, supported by Cancer Center Support Grant NCI CA060553. Also appreciated are Third Coast CFAR Viral Pathogenesis Core services (P30 AI117943); cryopreserved cells from the biorepository of U01 DA 036939; the expert dNTP quantitation and consultation from Peter L. Anderson, PharmD, at the Skaggs School of Pharmacy and Pharmaceutical Sciences of the University of Colorado Anschutz Medical Campus; advice from Leonidas C. Platanias, MD, PhD; and critical review of the manuscript by members of the Northwestern HIV Translational Research Center (Chisu Song and Gael Scholtes). Conceptualization, H.E.T.; Methodology & Experimental Design, H.E.T. E.M.C. and R.T.D.; Performance of Experiments, H.E.T. N.C. and D.L.; Formal Analysis, H.E.T. I.C. D.L. E.M.C. H.H. and R.T.D.; Writing ? Original Draft, H.E.T. and R.T.D.; Writing ? Review & Editing, H.E.T. N.C. D.L. I.C. E.M.C. H.H. and R.T.D.; Funding Acquisition, H.E.T. and R.T.D. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020 The Author(s)",
year = "2020",
month = jun,
day = "23",
doi = "10.1016/j.celrep.2020.107810",
language = "English (US)",
volume = "31",
journal = "Cell reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "12",
}
