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

Harry E. Taylor; Nina Calantone; Drew Lichon; Hannah Hudson; Isabelle Clerc; Edward M. Campbell; Richard T. D'Aquila

doi:10.1016/j.celrep.2020.107810

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

Harry E. Taylor^*, Nina Calantone, Drew Lichon, Hannah Hudson, Isabelle Clerc, Edward M. Campbell, Richard T. D'Aquila^*

^*Corresponding author for this work

Medicine, Infectious Diseases Division

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

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.

Original language	English (US)
Article number	107810
Journal	Cell reports
Volume	31
Issue number	12
DOIs	https://doi.org/10.1016/j.celrep.2020.107810
State	Published - Jun 23 2020

Funding

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).

Keywords

CD4 T cells
HIV-1
HIV-1 replication
host-virus interactions
immunometabolism
mTOR
mTORC1
mTORC2
microtubule stabilization
reverse transcription

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2020.107810

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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.",

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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.}",

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AU - Calantone, Nina

AU - Lichon, Drew

AU - Hudson, Hannah

AU - Clerc, Isabelle

AU - Campbell, Edward M.

AU - D'Aquila, Richard T.

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N2 - 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.

AB - 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.

KW - CD4 T cells

KW - HIV-1

KW - HIV-1 replication

KW - host-virus interactions

KW - immunometabolism

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KW - mTORC1

KW - mTORC2

KW - microtubule stabilization

KW - reverse transcription

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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