Abundance of Nef and p-Tau217 in brains of individuals diagnosed with HIV-associated neurocognitive disorders correlate with disease severance

Abstract

HIV-associated neurological disorders (HAND) is a term used to describe a variety of neurological impairments observed in HIV-infected individuals. The pathogenic mechanisms of HAND and of its connection to HIV infection remain unknown. Previous studies suggested that HIV-1 Nef may contribute to HAND by impairing cholesterol metabolism, increasing abundance of lipid rafts and affecting their functionality. Our comparative analysis of post-mortem brain samples demonstrated a trend towards decreased abundance of cholesterol transporter ABCA1 in samples from HIV-infected ART-treated individuals relative to samples from uninfected controls, and a reverse correlation between ABCA1 and flotillin 1, a marker for lipid rafts, in all analyzed samples. The brain samples from HIV-infected individuals, both with and without HAND, were characterized by increased abundance of p-Tau217 peptide, which correlated with the abundance of flotillin 1. HIV-1 Nef was detected in some, but not all, samples from HAND-affected individuals. Samples positive for Nef had lower abundance of ABCA1, higher abundance of flotillin 1 and p-Tau217, and were obtained from individuals with higher severity of HAND relative to Nef-negative samples. These results highlight the contribution of Nef and Nef-dependent impairment of cholesterol metabolism to the pathogenesis of HAND and support a connection between pathogenesis of HAND and Alzheimer disease.