Enhancing Novel Research for Inflammation and Cognitive Health among Adolescents and Young Adults Living with Perinatally Acquired HIV and Adversity (ENRICH+)

Neurocognitive impairment (NCI) is one of the most prevalent and deleterious complications observed in adolescents and young adults (AYA) with perinatally acquired HIV (PHIV), even despite viral suppression. Gaps in our current understanding of what drives NCI in virally suppressed people with PHIV greatly limit our ability to

develop targeted and tailored interventions for it. A growing body of research indicates that immune dysfunction (ID) may drive NCI in virally suppressed HIV. Peripheral blood markers of persistent and chronic ID (i.e., inflammation [e.g., CCL2, IL-8, and TNF-α] and immune activation [e.g., sCD14, sCD163]) are higher in people

with HIV and associated with NCI. The preponderance of this research, though, has been among adults with horizontally acquired HIV (HHIV) from high-income countries. HHIV is distinctly different than PHIV where infection began prior to physiological, immunological and brain development. Non-HIV sources of ID, such as

medical (e.g., malaria, SARS-COV-2), social (e.g., early trauma, stigma, poverty), and environmental (e.g., air pollution) adversities are also all independently associated with NCI but have been overlooked as potential modifiers of ID on NCI in HIV. Yet, many people with PHIV experience a high burden of these adversities,

especially in Uganda – where the proposed study will take place – and other countries in sub-Saharan Africa (SSA). Enduring multiple co-occurring adversities (i.e., syndemics) as well as timing, duration and type of ART, may affect the relationships between HIV and ID, and thus NCI, differently in PHIV vs HHIV, but research has

not addressed this. To date, most studies on ID and NCI in HIV have focused on host and genetic factors, while overlooking contextual factors known to contribute to ID and NCI. No studies to date have directly compared ID and NCI in AYA populations of the same age with PHIV and horizontally acquired HIV in SSA. Making this

comparison will allow us, for the first time, to delineate how lifelong HIV infection acquired prior to key physiological, immunological and brain development, as well as timing, duration and type of ART, may alter immune system responses and how NCI manifests in adolescence and young adulthood, as well as how

exposure to chronic adversity may affect the relationship between ID and NCI in HIV-infection. Addressing this knowledge gap is critical to developing targeted and developmentally appropriate interventions for NCI in AYA with PHIV, as the effects of exposure to individual and combined adversities may impact ID and NCI differently

in AYA with PHIV. Not only will this study help determine critical intervention targets for ID and NCI, it will also cohere a group of early and established Ugandan and US investigators focused on optimizing AYA outcomes and provide research opportunities and mentorship to medical, psychiatry and psychology students at Makerere

University for collaborative development of next-generation US and Ugandan trainees in brain health and ID across the lifespan.