HIV-1 Nef Reprograms Neuronal Lipid Rafts to Drive Neuroinflammation and Neurodegeneration in HIV-associated Neurocognitive Impairment

ABSTRACT: HIV-associated neurological disorders (HAND) remain a common co-morbidity of HIV infection. HIV protein Nef has been shown to increase the abundance of neuronal lipid rafts - cholesterol- and sphingolipid-rich membrane microdomains implicated in neurodegeneration and neuroinflammation. Here, we investigated how Nef-containing extracellular vesicles (exNef) secreted by glial cells influence the structural and functional properties of neuronal lipid rafts and contribute to HAND pathogenesis. Lipidomics analysis of isolated neuronal lipid raft fractions revealed minimal impact of exNef on the raft lipid composition; physico-chemical properties of the lipid rafts were also unaffected. In contrast, proteomic analysis revealed that among raft proteins with increased abundance following exNef exposure, ～25% were implicated in neurological disease pathways. Notably, this protein signature showed strong concordance with transcriptomic profiles from single-nucleus RNA sequencing (snRNA-seq) of brain from HIV-infected individuals. Targeted protein analysis unveiled that exNef promotes the redistribution of several neurodegenerative and inflammatory proteins to the lipid rafts, resulting in increased inflammation and apoptosis alongside reduced neuronal excitability. Pharmacological disruption of raft elevation with the lipid raft antagonist Oxy210 reversed exNef-induced raft expansion and abrogated these structural and functional alterations. In summary, exNef reorganize the neuronal lipid raft proteome, enhancing the activity of neurodegenerative and inflammatory mediators, thereby contributing to HAND pathogenesis.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Microglial Cell

DISEASE(S): Human Immunodeficiency Virus Infectious Disease

SUBMITTER: Angela Connolly  

LAB HEAD: Dmitri Sviridov

PROVIDER: PXD065713 | Pride | 2026-03-23

REPOSITORIES: Pride