Metabolically active CD4+ T cells expressing Glut1 and OX40 preferentially harbor HIV during in vitro infection

Clovis S Palmer; Gabriel A Duette; Marc C E Wagner; Darren C Henstridge; Suah Saleh; Candida Pereira; Jingling Zhou; David Simar; Sharon R Lewin; Matias Ostrowski; Joseph M McCune; Suzanne M Crowe

doi:10.1002/1873-3468.12843

Metabolically active CD4+ T cells expressing Glut1 and OX40 preferentially harbor HIV during in vitro infection

FEBS Lett. 2017 Oct;591(20):3319-3332. doi: 10.1002/1873-3468.12843. Epub 2017 Oct 11.

Authors

Clovis S Palmer^{1

2

3}, Gabriel A Duette⁴, Marc C E Wagner⁵, Darren C Henstridge⁶, Suah Saleh^{1

3}, Candida Pereira^{1

3

7}, Jingling Zhou¹, David Simar⁸, Sharon R Lewin^{2

9}, Matias Ostrowski⁴, Joseph M McCune¹⁰, Suzanne M Crowe^{1

2}

Affiliations

¹ Centre for Biomedical Research, Burnet Institute, Melbourne, Australia.
² Department of Infectious Diseases, Monash University, Melbourne, Australia.
³ Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia.
⁴ CONICET-Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Buenos Aires, Argentina.
⁵ AIDS Cure Research Collaborative, Pittsburgh, PA, USA.
⁶ Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
⁷ Monash Micro Imaging, Monash University, Melbourne, Australia.
⁸ Inflammation and Infection Research, School of Medical Sciences, University of New South Wales, Sydney, Australia.
⁹ The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Australia.
¹⁰ Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.

Abstract

High glucose transporter 1 (Glut1) surface expression is associated with increased glycolytic activity in activated CD4+ T cells. Phosphatidylinositide 3-kinases (PI3K) activation measured by p-Akt and OX40 is elevated in CD4+Glut1+ T cells from HIV+ subjects. TCR engagement of CD4+Glut1+ T cells from HIV+ subjects demonstrates hyperresponsive PI3K-mammalian target of rapamycin signaling. High basal Glut1 and OX40 on CD4+ T cells from combination antiretroviral therapy (cART)-treated HIV+ patients represent a sufficiently metabolically active state permissive for HIV infection in vitro without external stimuli. The majority of CD4+OX40+ T cells express Glut1, thus OX40 rather than Glut1 itself may facilitate HIV infection. Furthermore, infection of CD4+ T cells is limited by p110γ PI3K inhibition. Modulating glucose metabolism may limit cellular activation and prevent residual HIV replication in 'virologically suppressed' cART-treated HIV+ persons.

Keywords: HIV; mTOR; CD4 T cells; Glut1; PI3K; cancer; immunometabolism.

Publication types

Letter

MeSH terms

Adult
Anti-HIV Agents / therapeutic use*
Antiretroviral Therapy, Highly Active
CD4-Positive T-Lymphocytes / drug effects
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / metabolism*
CD4-Positive T-Lymphocytes / virology
Cell Proliferation
Class Ib Phosphatidylinositol 3-Kinase / genetics
Class Ib Phosphatidylinositol 3-Kinase / immunology
Gene Expression Regulation
Glucose Transporter Type 1 / genetics
Glucose Transporter Type 1 / immunology*
HIV Infections / drug therapy
HIV Infections / immunology
HIV Infections / metabolism*
HIV Infections / virology
HIV-1 / drug effects
HIV-1 / growth & development
Humans
Lymphocyte Activation
Male
Phosphoinositide-3 Kinase Inhibitors
Primary Cell Culture
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / immunology
Receptors, OX40 / genetics
Receptors, OX40 / immunology*
Signal Transduction
TOR Serine-Threonine Kinases / genetics
TOR Serine-Threonine Kinases / immunology
Virus Replication / drug effects

Substances

Anti-HIV Agents
Glucose Transporter Type 1
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
Receptors, OX40
SLC2A1 protein, human
TNFRSF4 protein, human
MTOR protein, human
Class Ib Phosphatidylinositol 3-Kinase
PIK3CG protein, human
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases

Grants and funding

P30 AI027757/AI/NIAID NIH HHS/United States