Extracellular vesicles carrying HIV-1 Nef induce long-term hyperreactivity of myeloid cells

Larisa Dubrovsky, Department of Microbiology, Immunology and Tropical Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20037, USA.
Beda Brichacek, Department of Microbiology, Immunology and Tropical Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20037, USA.
N M. Prashant, Department of Microbiology, Immunology and Tropical Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20037, USA.
Tatiana Pushkarsky, Department of Microbiology, Immunology and Tropical Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20037, USA.
Nigora Mukhamedova, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.
Andrew J. Fleetwood, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.
Yangsong Xu, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.
Dragana Dragoljevic, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia; Department of Immunology, Monash University, Clayton, VIC 3800, Australia.
Michael Fitzgerald, Lipid Metabolism Unit, Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Anelia Horvath, Department of Microbiology, Immunology and Tropical Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20037, USA.
Andrew J. Murphy, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia; Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, VIC 3052, Australia.
Dmitri Sviridov, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
Michael I. Bukrinsky, Department of Microbiology, Immunology and Tropical Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20037, USA. Electronic address: mbukrins@gwu.edu.

Document Type

Journal Article

Publication Date

11-22-2022

Journal

Cell reports

Volume

41

Issue

8

DOI

10.1016/j.celrep.2022.111674

Keywords

CP: Microbiology; HIV-1; HIV-associated co-morbidities; Nef; cholesterol biosynthesis; extracellular vesicles; inflammation; lipid rafts; monocyte-derived macrophages; trained immunity

Abstract

A possible explanation for chronic inflammation in HIV-infected individuals treated with anti-retroviral therapy is hyperreactivity of myeloid cells due to a phenomenon called "trained immunity." Here, we demonstrate that human monocyte-derived macrophages originating from monocytes initially treated with extracellular vesicles containing HIV-1 protein Nef (exNef), but differentiating in the absence of exNef, release increased levels of pro-inflammatory cytokines after lipopolysaccharide stimulation. This effect is associated with chromatin changes at the genes involved in inflammation and cholesterol metabolism pathways and upregulation of the lipid rafts and is blocked by methyl-β-cyclodextrin, statin, and an inhibitor of the lipid raft-associated receptor IGF1R. Bone-marrow-derived macrophages from exNef-injected mice, as well as from mice transplanted with bone marrow from exNef-injected animals, produce elevated levels of tumor necrosis factor α (TNF-α) upon stimulation. These phenomena are consistent with exNef-induced trained immunity that may contribute to persistent inflammation and associated co-morbidities in HIV-infected individuals with undetectable HIV load.

Department

Microbiology, Immunology, and Tropical Medicine

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