PROJECT SUMMARY / ABSTRACT Social connections are critical to human well-being, and people lacking in these connections (social isolation) or who perceive that they are lacking these connections (loneliness) have lower self-management of chronic disease, are more likely to suffer from substance abuse disorders and depression, and are at higher risk for premature mortality. People living with HIV report a significant burden of loneliness and other indicators of impaired social connectedness; these impaired social connections have been linked to reduced HIV adherence and quality of life. The significant strain imposed on social relationships by COVID-19 restrictions and by losses of family, friends, and community has brought urgency to the issue of social connections, particularly for vulnerable populations such as those living with HIV infection. COVID-19 has also brought increased calls for implementation of interventions focused on social connections, which in turn has highlighted a critical lack of effective interventions in this area, rooted in evidence gaps regarding relationships between social connection and health outcomes in diverse populations, in understanding of the unique and synergistic influences of conceptually distinct dimensions of social connection on health over time, and on modifiable pathways linking these connections to health outcomes. Applying a longitudinal, mixed-methods, and community-engaged framework within a nationally-representative and well-characterized HIV cohort study, the MACS/WIHS Combined Cohort Study (MWCCS), this project aims to: (Aim 1) characterize longitudinal and multidimensional patterns of social connection both prior to and during the COVID-era, and identify social, behavioral and genomic predictors of these patterns; (Aim 2) identify relationships between patterns of social connection and HIV outcomes, including identification of mechanistic pathways via substance use disorders and depression, and (Aim 3) assess multilevel mediators and moderators of relationships between social connection and temporally associated outcomes including area-level socio-geographic indicators of poverty and population density. This work utilizes the extensive platform of the MWCCS, including annual laboratory evaluation of HIV disease indices, validated medication adherence measures, genome-wide data that will be utilized to construct polygenic risk scores, annually updated geocoded data, and diagnostic assessments of substance use disorders and depression (N=2000). To this, we will add an annual battery of social connection measures, including social and emotional loneliness, social isolation, and social integration at selected MWCCS sites (N=735), coupled with nested, longitudinal qualitative interviews (N=40). This multidimensional, longitudinal and multilevel analysis will significantly extend previous research in this area, and findings from this project can be utilized to identify actionable targets to support the design of effective interventions in this important area and high priority population.

PROJECT NARRATIVE Social connections are critical to human well-being, and people lacking in actual connections or who perceive that they are lacking these connections are more likely to suffer from substance abuse disorders and other mental health problems, and among those living with HIV infection, to have lower medication adherence and decreased quality of life. Applying a longitudinal, mixed-methods, and community-engaged framework in a nationally-representative study of persons living with HIV, and encompassing patterns of social connection both prior to and during the COVID-era, this project will examine understudied pathways linking social connections to substance use disorders and depression, and to HIV outcomes. A better understanding of these mechanisms will address a critical gap in the literature on social connections and will advance the ability to design effective interventions in this important area.