Cardiac function and proteomic biomarkers in individuals with perinatal HIV infection or exposure

About This Grant

There are approximately three million individuals with perinatally acquired human immunodeficiency virus (pnHIV) worldwide and >150,000 new youth with pnHIV (YpnHIV) annually. The incidence of pnHIV has declined dramatically over the last two decades, yet rates remain high in Eastern and Southern sub-Saharan Africa (SSA) - threefold greater than the global average. Prior studies from SSA have been unable to resolve whether pnHIV increases risk of cardiac or physical dysfunction compared to unexposed children or those with perinatal HIV exposure but who are HIV seronegative (PHEU). Elucidating determinants of cardiac, autonomic and physical dysfunction in the disproportionately affected population of YpnHIV is critical to identify, treat and prevent cardiac comorbidities. Comprehensive phenotyping that combines cardiac imaging, physical function assessment, autonomic dysfunction and molecular profiling represents an innovative approach to fully characterizing the earliest manifestations of subclinical disease thereby enabling early intervention. Thus, the overall objectives of this application are to identify imaging and proteomic determinants of cardiac dysfunction in YpnHIV compared to the HIV unexposed (HU), and to evaluate effects of YpnHIV on physical performance and heart rate variability. Our central hypothesis is that YpnHIV have worse cardiac and physical function compared to HU and PHEU. Our hypothesis builds on our preliminary data which identified a high burden of early cardiac dysfunction on echocardiogram among YpnHIV, and preliminary data linking subclinical cardiac dysfunction among YpnHIV to proteomic profiles indicating cardiac fibrosis, inflammation, and immune activation from a large HIV care program in western Kenya. We will test our central hypothesis through the following Specific Aims: (1) Determine if pnHIV is associated with cardiac dysfunction and abnormal physical performance in children and young adults; (2) Identify mechanisms of subclinical cardiac dysfunction and related biomarkers in YpnHIV using high-throughput proteomic profiling; (3) Measure the effect of HIV status on longitudinal change in cardiac and physical function during a period of rapid adolescent growth. To achieve our Aims, we will conduct a prospective study of a total of >400 YpnHIV, PHEU and HU in western Kenya who are engaged in a long-term, population-based HIV clinical care program – the Academic Model Providing Access to Healthcare (AMPATH) Kenya Program. We will perform echocardiograms, a clinical assessment, six-minute walk testing, heart rate variability assessment and collect biospecimens for molecular profiling through proteomics. In a sub-sample, we will repeat measures at 24 months to determine whether YpnHIV, PHEU and HU status impacts progression of cardiac or physical dysfunction. Our scientific contribution is expected to be significant because we are addressing a dire health comorbidity for YpnHIV with deep clinical, imaging, functional and biomarker phenotyping in an endemic population. As a consequence of the work proposed, we expect to uncover novel insights and a deeper understanding of the pathobiology of contemporary HIV-related cardiovascular comorbidities.