Neuro-HIV-New insights into pathogenesis and emerging therapeutic targets

Document Type

Journal Article

Publication Date

12-1-2023

Journal

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Volume

37

Issue

12

DOI

10.1096/fj.202301239RR

Keywords

HAND; HIV; Nef; cholesterol; epigenetic modifications; extracellular vesicles; inflammation; lipid rafts; trained immunity

Abstract

HIV-associated neurocognitive disorders (HAND) is a term describing a complex set of cognitive impairments accompanying HIV infection. Successful antiretroviral therapy (ART) reduces the most severe forms of HAND, but milder forms affect over 50% of people living with HIV (PLWH). Pathogenesis of HAND in the ART era remains unknown. A variety of pathogenic factors, such as persistent HIV replication in the brain reservoir, HIV proteins released from infected brain cells, HIV-induced neuroinflammation, and some components of ART, have been implicated in driving HAND pathogenesis in ART-treated individuals. Here, we propose another factor-impairment of cholesterol homeostasis and lipid rafts by HIV-1 protein Nef-as a possible contributor to HAND pathogenesis. These effects of Nef on cholesterol may also underlie the effects of other pathogenic factors that constitute the multifactorial nature of HAND pathogenesis. The proposed Nef- and cholesterol-focused mechanism may provide a long-sought unified explanation of HAND pathogenesis that takes into account all contributing factors. Evidence for the impairment by Nef of cellular cholesterol balance, potential effects of this impairment on brain cells, and opportunities to therapeutically target this element of HAND pathogenesis are discussed.

Department

Microbiology, Immunology, and Tropical Medicine

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