HIV Complex Causal Modeling: Gut Microbiome, Drug Use, and Immune Responses

PROJECT SUMMARY/ABSTRACT Human immunodeficiency virus (HIV) acquisition often co-occurs with drug use disorders (DUD), particularly in the context of injected drug use. Individuals with DUD or those living with HIV/AIDS have been found to commonly experience changes in the balance of gut microbiota (GM) in their gastrointestinal tract.

The gut, which is considered the body's largest immune organ, harbors trillions of microorganisms that influence how our body responds to neurological and immune challenges or inflammation. Thus, DUD, HIV, GM, and immune responses form a complex interplay, influencing each other. To elucidate the causal relationship of HIV acquisition, we will leverage genome-wide association studies

(GWAS) summary statistics and existing datasets. Our primary analytical strategy involves employing Mendelian randomization (MR) combined with mediation analysis. Utilizing MR analysis, which relies on GWAS summary statistics, we will deploy static GWAS-identified genetic markers as instrumental variables to

address confounding factors while inferring causal effects. We will examine four distinct DUDs, including use disorders of cannabis, cocaine, tobacco, and opioids. Our investigation will analyze a large-scale human GM GWAS, GWAS of target immune-related biomarkers, and our ongoing HIV GWAS. Within the MR framework,

our outcome trait is HIV acquisition, and DUDs are exposure variables. Through univariate MR and multivariate MR, we aim to identify drug-specific causal effects on HIV risk and immune responses. We will also investigate genetic correlations among these traits. Furthermore, we will infer the causal mediation relationship among

DUD, GM, and immune responses in HIV risk, providing insights through the assessment of causality and mediation effects. In summary, finding causal effects between DUD and HIV acquisition is essential for designing effective prevention and intervention strategies, guiding public health policies, understanding the

mechanisms involved, and ultimately reducing the burden of HIV in populations affected by drug use.