Genetic Polymorphisms &amp; Neurocognitive Vulnerability in HIV
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Cognitive deficits continue to occur at a significant frequency among those with HIV despite the success of antiretroviral medicines. It is now recognized that the deficits, ranging from mild impairments to debilitating dementia, are largely due to compromise of the dopaminergic fronto-striatal system of the brain. Thus far, NeuroAIDS research has focused on neuropathological, immunologic, and psychosocial factors, as well as medical co-morbidities, as contributors to the development of cognitive deficits in HIV. While this research has been invaluable in elucidating the etiology of HIV-associated cognitive disorders, the variation in the risk for these disorders indicate that additional factors exist which determine vulnerability. One factor may be host genetic variation. Specific genetic polymorphisms (GPs) have been shown to be endogenous risk factors for neuropsychiatric disease, and polymorphisms that alter dopaminergic functioning appear to explain significant variation in cognitive functioning across both healthy and clinical populations. Such findings are relevant to NeuroAIDS research, as information about the host genotype may add a new tier of explanatory power to the current model of neuropathogenesis in HIV, which has heretofore stressed a study of virus genotype. In the current application, we propose to examine the contribution of GPs that affect the metabolism and activity of dopamine (DA) in the risk for neurobehavior disorders and deficits. We will employ regression analyses to examine the contribution of both exogenous factors (HIV and stimulant dependence) and endogenous vulnerability (genotype) to the risk for cognitive deficit and/or HIV-associated neurocognitive disorders. We include stimulant dependence due to its high co-morbidity with HIV and because stimulants can profoundly affect the subcortical DA pathways of the brain. In addition, the high comorbidity of stimulant abuse/dependence and HIV in California make examination of this relationship highly relevant. Aside from the potential importance of this study with regards to NeuroAIDS research, its strength lies in its use of existing resources. We will draw from existing tissue and data from the National NeuroAIDS Tissue Bank (NNTC). The NNTC database contains detailed cognitive, neurologic, and medical data for over 1700 HIV+ individuals. Tissue will be processed at the UCLA Biological Samples Processing and Sequencing &amp; Genotyping Cores, which use state-of-the-art equipment to process the tissue samples, allowing us to examine a number of known GPs. Additional DNA will be stored for future analyses, as we view this as an initial probe into the relationship between host genotype and neurocognitive outcomes in HIV. The study will be spearheaded by a team with expertise in neuropsychology, neurology, genetics, virology, and biostatistics, all of who have extensive research experience in HIV infection and/or genetics of cognitive disorders. Elucidating the contribution of genotype to cognitive vulnerability in HIV is great; such understanding could lead to more empirically-based preventative strategies and target-specific pharmaceutical interventions. Further, because the proposed study aims to examine a sample that is typical of California’s HIV+ population, with consideration of ethnic and health-related factors common to this state, our findings will be directly relevant and beneficial to both Californians and HIV+ individuals in general.