Molecular pathophysiology of HIV among acutely ill children in sub-Saharan Africa

Despite improved prevention of mother-to-child transmission of infections, human immunodeficiency virus (HIV) still accounts for a considerable number of new infections among children in sub-Saharan Africa. HIV infected children in low-resource settings normally present with comorbidities including severe wasting and stunting, anorexia, diarrhoea, and coinfections, and are at increased risk of mortality, morbidity, and poor nutritional recovery compared to HIV-negative children from the same settings. The molecular mechanisms underlying such outcomes among these children remain unclear limiting the development of new interventions that may improve outcomes. This study will investigate how HIV-specific biological processes influence mortality and growth outcomes among children during and after acute illness in sub-Saharan Africa. I hypothesize that there are specific biological processes associated with HIV several of which are microbially driven and associated with poor clinical outcomes in children. Existing clinical data and samples from The Childhood Acute Illness and Nutrition (CHAIN; Kenya, Uganda, Malawi) Network and The Health Outcomes, Pathogenesis and Epidemiology of Severe Acute Malnutrition (HOPE-SAM; Zambia and Zimbabwe) cohorts will be used. Systemic proteome, metabolome, lipopolysaccharides, intestinal microbiome, targeted pathogens, and biomarkers of enteropathy have been determined for the admission and discharge time points within CHAIN. Longitudinal analyses using existing samples in the two cohorts will be undertaken to target specific persisting biological processes. Bioinformatics and statistical analysis approaches will be used. Potential mechanistic pathways will be determined by pathway enrichment analysis of the signatures obtained from the models. Findings from this study will inform targetable mechanisms for intervention to improve outcomes among HIV-infected children.