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How HIV infection may contribute to wide-ranging metabolic conditions

July 25, 2019

HIV-infected cells release vesicles that contain a viral protein called Nef, impairing cholesterol metabolism and triggering inflammation in uninfected bystander cells, according to a study published July 25 in the open-access journal PLOS Pathogens by Dmitri Sviridov of the Baker Heart and Diabetes Institute in Australia, and colleagues. The findings may explain how HIV infection causes a wide range of conditions that are associated with dysfunction in uninfected cells.

HIV infects only a limited repertoire of cells expressing HIV receptors. But HIV infection is also associated with conditions involving the dysfunction of cells that cannot be infected by HIV, such as hardening of the arteries, dementia, kidney impairment, and certain heart problems. These HIV-associated conditions persist even after successful application of antiretroviral therapy, when no virus is found in the blood. Many of these conditions involve impairments in cholesterol metabolism. In the new study, Sviridov and colleagues examined the mechanisms that may contribute to HIV-associated metabolic conditions.

The results showed that the HIV protein Nef is released from infected cells in vesicles that are then rapidly taken up by uninfected bystander white blood cells, impairing cholesterol metabolism in these cells. This impairment causes the formation of excessive lipid rafts -- discrete lipid domains present in the external leaflet of the plasma membrane - and the re-localization of inflammatory receptors into rafts, triggering inflammation. The findings demonstrate how a single viral molecule released from infected cells into circulation may contribute to a range of pathogenic responses.

The authors add, "Our study points to a common mechanism of various co-morbidities of HIV infection. This opens a possibility to target this mechanism using drugs affecting cholesterol metabolism to treat several co-morbidities in people living with HIV."
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Research Article

Funding: The study was supported by the grants from the National Institutes of Health (http://www.nih.gov) (HL131473 to MB and DS) American Heart Association (http://www.heart.org) (17GRNT33630163 to MB) and National Health and Medical Research Council of Australia (http://www.nhmrc.dov.au) (GNT1036352 to DS and MB) and supported in part by the Victorian Government's OIS Program (DS) and by District of Columbia Centre for AIDS Research (DC CFAR), an NIH-funded program (5P30 AI055019, to MB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Competing Interests: The authors have declared that no competing interests exist.

Citation: Mukhamedova N, Hoang A, Dragoljevic D, Dubrovsky L, Pushkarsky T, Low H, et al. (2019) Exosomes containing HIV protein Nef reorganize lipid rafts potentiating inflammatory response in bystander cells. PLoS Pathog 15(7): e1007907. https://doi.org/10.1371/journal.ppat.1007907

Author Affiliations:

Baker Heart and Diabetes Institute, Melbourne, Australia
Department of Immunology, Monash University, Melbourne, Australia
Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC, United States of America
Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
Department of Medicine, University of California San Diego, La Jolla, CA, United States of America

In your coverage please use this URL to provide access to the freely available paper: http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1007907

PLOS

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