Novel pathogenic mechanism of HIV-associated CNS neurological disorders

Abstract
Effective treatment of HIV infection has reduced the severity of HIV-associated neurocognitive disorder (HAND),
however, the incidence of CNS neurological dysfunction (~50% of HIV patients) has not been diminished by the
treatment. With dramatically extended life expectancy of HIV-infected patients, neurological dysfunction reduces
the quality of life by affecting learning and executive functions, and puts these individuals at risk of developing
significant health problem. The treatment options for this co-morbidity are limited by poor understanding of its
pathogenic mechanisms in virologically suppressed patients. Several hypotheses have been suggested, ranging
from low grade chronic neuroinflammation caused by HIV infection, to neurotoxicity of HIV-related factors, to HIV
accelerating the natural development of known neurodegenerative diseases, such as Alzheimer’s disease.
Although these hypotheses are consistent with some elements of HAND, none of them explains the full
pathological manifestation of this disorder and its unique relationship with HIV infection. In this application, we
propose to test a novel hypothesis that, if confirmed, will point to the key element of pathogenesis of CNS
neurological disorder caused by HIV infection and may translate to novel treatment opportunities. We
hypothesize that the central mechanism in HIV-associated CNS disorder is the reorganization of lipid
rafts caused by HIV Nef. Changes in neuronal lipid rafts promote protein misfolding/aggregation,
exacerbate inflammatory responses, and affect neuronal communications leading to functional
impairment and eventually to neurodegeneration. Dysfunction of the lipid rafts is essential for pathogenesis
of many neurodegenerative diseases, including Alzheimer’s, pointing to a broad relevance of our hypothesis to
diseases of aging population. This hypothesis is based on our published and preliminary findings that HIV protein
Nef reorganizes lipid rafts in macrophages and neurons. We recently demonstrated that changes to lipid rafts
inflicted by Nef are similar to those found in neurons infected by prions. Importantly, recent studies have shown
that neurons exposed to Nef-containing exosomes, released by HIV-infected brain macrophages, microglia and
astrocytes, take up exogenous Nef, which is functionally active. Nef production in viral reservoirs, including brain,
continues in the presence of antiretroviral therapy. The following aims will be pursued to test this innovative
hypothesis. Aim 1: To establish the contribution of Nef to HIV-associated CNS neurological dysfunction in mouse
models; Aim 2: To determine mechanisms by which Nef released from HIV-infected cells affects cholesterol
metabolism in neurons, causing neurological dysfunction; Aim 3: To target lipid rafts as a potential therapeutic
approach to treat HIV-associated neurological dysfunction. These interconnected but independent aims will
provide an actionable model of HIV-associated CNS disorder.

Grant Number: 5R01NS124477-05
NIH Institute/Center: NIH
Principal Investigator: MICHAEL BUKRINSKY