Stress-immune mechanisms for people living with HIV, CUD and Depression

Psychosocial stress profoundly affects neuroendocrine (hypothalamic-pituitary-adrenal, HPA) and immune function in both central and peripheral cells. People living with HIV (PLWH) show heightened distress and increased inflammatory burden, leading to greater complex morbidity (CM) including high prevalence of cannabis use disorder (CUD) and major depressive disorders (MDD). However, the mechanisms governing stress-immune interactions in PLWH, and their associated distress and drug use are not well understood. Notably, MDD and CUD each disrupts HPA-immune responses but their effects on stress-related HPA-immune function and homeostasis in PLWH are not known. Epigenetic aberrant of the “stress genome” has been shown to disrupt HPA function and stress adaptation. In the HIV infected host genome, the epigenome landscape is profoundly altered by HIV-1, including genes that are part of the stress genome, highlighting the interactive role of the stress and immune genomes in development of CM in PLWH. But the epigenetically regulated gene expression of stress-immune effects in PLWH with MDD and CUD has not been studied. This proposal aims to address these research gaps using a powerful and novel cross-diagnostic approach with multiple complementary approaches to examine the overarching hypothesis that PLWH+CM exhibit impaired stress-related HPA and HPA- immune function due to alterations in epigenetic mechanisms, and that these stress-related HPA- immune and related epigenetic maladaptations predict distress, craving and substance use symptoms underlying CM in PLWH. In this study, we defined complex morbidity as PLWH with CUD and MDD. This hypothesis will be tested using a combined human experimental approach with prospective longitudinal assessment of daily distress, and substance use symptoms as well as assessment of chronic stress (C-stress), social determinants of health, and resilience in the experimental cohort with corroboration in a population-based analysis of a well-established large cohort of PLWH. We aim to 1) Determine HPA and immune response to acute stress among 40 healthy controls (HC), 40 PLWH, and 40PLWH+CM by experimentally stress-challenging all participants and measure HPA-immune for each participant; 2) Identify cell-type epigenetic regulation of HPA- immune response to acute stress in 3 groups by profiling the DNA methylome (DNAm) and transcriptome at 3 timepoints for each subject in bulk blood cells following the deconvolution of DNAm and RNA expression to five major cell types. snRNA-seq and snATAC-seq will be conducted in a subset of samples; 3) Link acute stress HPA-immune dysregulation to retrospective stress and prospective future daily subjective distress and CM symptoms in the real world by using ecological momentary assessment. We will explore demographic and individual differences in psychosocial stress, acute stress-immune response and identify potential biomarkers of PLWH+CM. If successful, this project will not only identify new psychobiological-epigenomic mechanisms for PLWH+CM but also identify stress biomarkers in PLWH to predict who is most susceptible to complex morbidities.