Pharmacogenomics of HIV Therapy

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PROJECT SUMMARY Approximately 1.2 million individuals in the United States and 38 million worldwide are living with HIV. Priorities for HIV research include cure, mitigating associated inflammation and immune activation, novel therapeutics, and optimizing current management. In addition, there remains detrimental interindividual variability in HIV treatment responses regarding toxicities and immune recovery. Efforts to decipher relationships between the human genome and responses to therapeutic interventions in people living with HIV will help drive continued progress in the field, and involve complementary methodologies. The well-established value of the genome- wide association study (GWAS) is expanded by considering the polygenic risk score (PRS), which considers numerous polymorphisms that, in combination, affect risk for a phenotype, and by the integrated risk score (IRS), which combines PRS with non-genetic exposures. It is further expanded by the transcriptome-wide association study (TWAS), which relies on heritable gene expression in over 40 tissues throughout the body, inferred from genome-wide genotype data, and by the phenome-wide association study (PheWAS), which simultaneously interrogates genotype-phenotype associations across vast numbers of phenotypes. Complementing these variant-based and gene-based approaches are powerful wet-lab direct bulk and single- cell transcriptome analyses (TA) that decipher underlying biology by comparing patterns of gene expression between different experimental conditions or phenotypes. Building on progress to date, we will apply these complementary approaches to decipher genetic underpinnings of HIV-relevant clinical and endophenotypes, largely through analyses of available data and specimens from numerous different AIDS Clinical Trials Group trials and cohorts. We will consider interventions that target inflammation, the HIV reservoir, viral replication, and beyond. This work is facilitated by extensive groundwork laid by the proposing investigators to create and implement efficient, robust systems for variant-based, gene-based, and RNA expression-based genomic data generation and data analysis, as well as interpretation and visualization of results. Our ultimate goal is to improve the lives of people living with HIV through accelerated discovery based on state-of-the-art genomic approaches.