R01NS124477

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, which affects approximately 50% of HIV patients, has not been diminished by the treatment. With the 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 problems. 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 the pathogenesis of many neurodegenerative diseases, including Alzheimer's, pointing to a broad relevance of our hypothesis to diseases of the 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 the 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.

George Washington University (The)

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

Washington, District Of Columbia 200520011 United States

Single Zip Code

HIV Infection of the Central Nervous System (R01 Clinical Trial Not Allowed) (PA-20-149)

Amendment Since initial award the total obligations have increased 396% from $730,589 to $3,625,378.