Genetic Polymorphisms and Neurocognitive Vulnerability in HIV

Andrew J. Levine, UC Los Angeles

Anti-retroviral therapy has greatly curbed HIV proliferation; however cognitive deficits continue to have a high prevalence among the infected. Converging evidence from neuropsychological, neurophysiological, and autopsy studies implicate dysfunction of the dopaminergic fronto-striatal system of the brain as the basis for these deficits. However, neuropathological changes do not consistently correlate with impairment, as some individuals are more vulnerable to developing neurocognitive disorders and deficits than others. This suggests that as of yet unknown variables mediate this relationship. In the current application, we propose to examine the contribution of genetic polymorphisms (GPs) that affect the metabolism and activity of dopamine (DA), a key neurotransmitter in the fronto-striatal. Consistent with current theories of Gene X Environmental interactions in development of psychiatric illness, we will consider both endogenous (GPs) and exogenous (HIV and stimulant use) factors in the development of neurocognitive disorders and/or deficits in HIV.

It is well established that both HIV and stimulant use are exogenous stressors that adversely affect the subcortical dopaminergic pathways of the brain. More recently, studies have shown that certain GPs that affect DA metabolism are risk factors for neuropsychiatric disease, and that they also explain significant variation in cognitive functioning across both healthy and clinical populations. Such findings are relevant to NeuroAIDS research, as information about host genotype may add a new tier of explanatory power to the current model of neuropathogenesis in HIV-related neurocognitive disorders. Our proposed study may help explain why some individuals with HIV, despite having stable immune functioning, experience cognitive decline while others do not.

The potential value of elucidating the contribution of genotype to neurocognitive vulnerability in HIV is great; such understanding could lead to more empirically-based preventative strategies and target-specific pharmaceutical interventions. With the new technologies available to quickly and inexpensively obtain patient genotype, the opportunity to determine tailored therapeutic interventions is upon us. In addition, using information about host-genotype in developing preventative strategies has the potential to save lives and health-related resources, as well as reducing the financial burden of HIV-related cognitive disorders on the state of California.

Towards this end, we have assembled a multidisciplinary team composed of investigators with expertise in neuropsychology, neurology, genetics, and virology, all who have extensive research experience in HIV infection and/or genetics of neurocognitive disorders. Using existing tissue and data from the National NeuroAIDS Tissue Bank (NNTC), we will have the ability to examine a number of known GPs in relation to HIV-related neurocognitive disorders and deficits. Using regression modeling, we will be able to examine the degree of risk that various endogenous and exogenous variables confer for neurocognitive disorder and/or deficit. This study, focusing on DA-related GPs, will be an initial probe into this relationship, as in the future we plan to examine additional GPs and their relation to neurocognitive outcomes. We are confident that the results of this study will lead to additional funding opportunities through the National Institutes of Health.