Multi-omics analyses reveal that HIV-1 alters CD4+ T cell immunometabolism to fuel virus replication

Haitao Guo; Qi Wang; Khader Ghneim; Li Wang; Elena Rampanelli; Elizabeth Holley-Guthrie; Liang Cheng; Carolina Garrido; David M Margolis; Leigh A Eller; Merlin L Robb; Rafick-Pierre Sekaly; Xian Chen; Lishan Su; Jenny P-Y Ting

doi:10.1038/s41590-021-00898-1

Multi-omics analyses reveal that HIV-1 alters CD4⁺ T cell immunometabolism to fuel virus replication

Nat Immunol. 2021 Apr;22(4):423-433. doi: 10.1038/s41590-021-00898-1. Epub 2021 Mar 25.

Authors

Haitao Guo^#^{1

2}, Qi Wang^#¹, Khader Ghneim³, Li Wang⁴, Elena Rampanelli¹, Elizabeth Holley-Guthrie^{1

2}, Liang Cheng¹, Carolina Garrido⁵, David M Margolis⁵, Leigh A Eller^{6

7}, Merlin L Robb^{6

7}, Rafick-Pierre Sekaly³, Xian Chen^{1

4}, Lishan Su^{8

9

10}, Jenny P-Y Ting^{11

12

13}

Affiliations

¹ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
² Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³ Department of Pathology, Emory University, Atlanta, GA, USA.
⁴ Department of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵ HIV Cure Center and Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁶ US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
⁷ Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
⁸ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. [email protected].
⁹ Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA. [email protected].
¹⁰ Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. [email protected].
¹¹ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. [email protected].
¹² Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. [email protected].
¹³ Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. [email protected].

^# Contributed equally.

Abstract

Individuals infected with human immunodeficiency virus type-1 (HIV-1) show metabolic alterations of CD4⁺ T cells through unclear mechanisms with undefined consequences. We analyzed the transcriptome of CD4⁺ T cells from patients with HIV-1 and revealed that the elevated oxidative phosphorylation (OXPHOS) pathway is associated with poor outcomes. Inhibition of OXPHOS by the US Food and Drug Administration-approved drug metformin, which targets mitochondrial respiratory chain complex-I, suppresses HIV-1 replication in human CD4⁺ T cells and humanized mice. In patients, HIV-1 peak viremia positively correlates with the expression of NLRX1, a mitochondrial innate immune receptor. Quantitative proteomics and metabolic analyses reveal that NLRX1 enhances OXPHOS and glycolysis during HIV-1-infection of CD4⁺ T cells to promote viral replication. At the mechanistic level, HIV infection induces the association of NLRX1 with the mitochondrial protein FASTKD5 to promote expression of mitochondrial respiratory complex components. This study uncovers the OXPHOS pathway in CD4⁺ T cells as a target for HIV-1 therapy.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antiviral Agents / pharmacology
CD4-Positive T-Lymphocytes / drug effects
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / metabolism
CD4-Positive T-Lymphocytes / virology*
Disease Models, Animal
Female
Gene Expression Profiling
Gene Regulatory Networks
Genomics*
HEK293 Cells
HIV Infections / drug therapy
HIV Infections / immunology
HIV Infections / metabolism
HIV Infections / virology*
HIV-1 / drug effects
HIV-1 / growth & development*
HIV-1 / immunology
HIV-1 / metabolism
Host-Pathogen Interactions
Humans
Jurkat Cells
Male
Metabolome*
Metabolomics*
Metformin / pharmacology
Mice
Mitochondrial Proteins / genetics
Mitochondrial Proteins / metabolism
Oxidative Phosphorylation* / drug effects
Proteome*
Proteomics
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism
Transcriptome*
Viral Load
Virus Replication* / drug effects

Substances

Antiviral Agents
Mitochondrial Proteins
NLRX1 protein, human
Proteome
RNA-Binding Proteins
TBRG4 protein, human
Metformin

Abstract

Publication types

MeSH terms

Substances

Grants and funding