Abundance of Nef and p-Tau217 in Brains of Individuals Diagnosed with HIV-Associated Neurocognitive Disorders Correlate with Disease Severance.

HIV-associated neurocognitive 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, but one of the considered hypotheses suggests that HIV infection accelerates the development of Alzheimer's disease. Previous studies suggested that HIV-1 Nef may contribute to HAND by inhibiting cholesterol efflux, increasing the abundance of lipid rafts, and affecting their functionality. Our comparative analysis of postmortem brain samples demonstrated a trend toward the 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 the increased abundance of p-Tau217 peptide, which correlated with the abundance of flotillin 1. HIV-1 Nef was analyzed in samples from HAND-affected individuals by Western blot with 4 different antibodies and by LC-MS/MS, producing a Nef-positivity score. A significant correlation was found between this score and the abundance of flotillin 1, the abundance of p-Tau217, and the severity of HAND. These results highlight the contribution of Nef and Nef-dependent impairment of cholesterol efflux to HAND pathogenesis and support a connection between the pathogenesis of HAND and Alzheimer's disease.