Genetic Predisposition and Pharmacogenomics of HIV-Associated Cognitive Impairment

总结

SUMMARY With the introduction of potent antiretroviral therapy (ART), HIV is now manageable as a chronic disease, with improved life expectancy of people with HIV (PWH). However, despite viral suppression, high rates of comorbidities in PWH persist, due to a complex interplay between HIV, host genetics, inflammation, and chronic viral infections. Understanding the role of genetic susceptibility to common diseases or drug responses to ART could improve drug efficacy and reduce comorbidities. In our parent grant, we leveraged a large well- characterized prospective cohort of PWH in care in the U.S (CNICS, Centers for AIDS Research Network of Integrated Clinical Systems) with longitudinal clinical data to characterize the genetic landscape of a variety of comorbidities and adverse side effects associated with ART, including liver disease, kidney disease, atherosclerosis and osteonecrosis. However, in addition to these conditions, neurocognitive deficits also are a pronounced consequence of HIV/AIDS. HIV-1 infection targets the central nervous system and leads to high rates of delirium, depression, opportunistic central nervous system infections, and dementia. Long-term HIV replication in the brain occurs in astrocytes and microglia, allowing the virus to hide from ART and later compromise neuronal function. Cognitive impairment (CI) in PWH, culminating in Alzheimer's disease (AD), is becoming an increasingly important issue as this population ages. HIV-associated mild to moderate CI affects up to 50% PWH and results in lower quality of life, poorer adherence to medication, increased unemployment and reduced life expectancy. The pathogenic mechanisms causing CI are often multifactorial, including complex immunopathological processes controlled by HIV factors, the direct effects of ART, and genetic predisposition. This supplement will leverage CNICS and the extensive data generated by the parent grant to further understand genetic determinants of CI among PWH. We will use the digit symbol substitution neurocognitive test (DSST), widely used to measure CI due to brevity, reliability, and consistent performance across language, cultural and educational differences. We will: 1) Evaluate neurocognitive status in ethnically diverse PWH and identify genetic determinants of CI. We will oversee the completion of the DSST from the Brain Health Assessment, a computer-delivered, full cognitive assessment, in >1000 PWH with existing genome-wide genotype data and evaluate the relationship between their neurocognitive status and a series of polygenic risk scores for AD, dementias, and other cognitive traits. 2) Using systems pharmacology approach, identify biological pathways and related key driver genes through which various ART regimens may promote cognitive decline. We will treat neuronal cell lines with ART and search for the overlap between ART-induced transcriptional responses and gene networks associated with AD and dementias. Variants in the key driver genes will be evaluated in association with cognitive phenotypes in CNICS. This proposal is within the scope of the parent grant and will help generate new valuable phenotype data to advance the field of AD and dementia.