HIV-1 Nef is carried on the surface of extracellular vesicles

Christophe Vanpouille, Section on Intercellular Interactions, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
Beda Brichacek, Department of Microbiology, Immunology and Tropical Medicine, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA.
Tatiana Pushkarsky, Department of Microbiology, Immunology and Tropical Medicine, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA.
Larisa Dubrovsky, Department of Microbiology, Immunology and Tropical Medicine, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA.
Wendy Fitzgerald, Section on Intercellular Interactions, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
Nigora Mukhamedova, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.
Sofia Garcia-Hernandez, Nanofabrication and Imaging Center, The George Washington University, Washington, District of Columbia, USA.
Doreen Matthies, Unit on Structural Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
Anastas Popratiloff, Nanofabrication and Imaging Center, The George Washington University, Washington, District of Columbia, USA.
Dmitri Sviridov, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.
Leonid Margolis, Section on Intercellular Interactions, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
Michael Bukrinsky, Department of Microbiology, Immunology and Tropical Medicine, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA.

Document Type

Journal Article

Publication Date

7-1-2024

Journal

Journal of extracellular vesicles

Volume

13

Issue

7

DOI

10.1002/jev2.12478

Keywords

ELISA; HIV‐1; Nef; extracellular vesicles

Abstract

Extracellular vesicles (EVs) serve as pivotal mediators of intercellular communication in both health and disease, delivering biologically active molecules from vesicle-producing cells to recipient cells. In the context of HIV infection, EVs have been shown to carry the viral protein Nef, a key pathogenic factor associated with HIV-related co-morbidities. Despite this recognition, the specific localisation of Nef within the vesicles has remained elusive. This study addresses this critical knowledge gap by investigating Nef-containing EVs. Less than 1% of the total released Nef was associated with EVs; most Nef existed as free protein released by damaged cells. Nevertheless, activity of EV-associated Nef in downregulating the major cholesterol transporter ABCA1, a critical aspect linked to the pathogenic effects of Nef, was comparable to that of free Nef present in the supernatant. Through a series of biochemical and microscopic assays, we demonstrate that the majority of EV-associated Nef molecules are localised on the external surface of the vesicles. This distinctive distribution prompts the consideration of Nef-containing EVs as potential targets for immunotherapeutic interventions aimed at preventing or treating HIV-associated co-morbidities. In conclusion, our results shed light on the localisation and functional activity of Nef within EVs, providing valuable insights for the development of targeted immunotherapies to mitigate the impact of HIV-associated co-morbidities.

Department

Microbiology, Immunology, and Tropical Medicine

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