There are approximately 2.1 million children and adolescents living with HIV (CAHIV) worldwide. Most of these children (1.8 million) reside in sub-Saharan Africa and acquired HIV perinatally. With antiretroviral therapy (ART), CAHIV can now achieve near normal life-expectancy, but with that comes risk of non-AIDS comorbidities. Importantly, it is unknown is whether CAHIV with perinatal HIV infection are at increased risk of cardiac dysfunction compared to uninfected children, as has been observed in adults. Thus, the long-term goals of this proposal are to detect and prevent cardiac dysfunction in CAHIV. The overall objectives are to identify clinical and biomarker determinants of cardiac dysfunction in CAHIV compared to uninfected children. Our central hypothesis is that HIV infection is associated with worse cardiac function compared to HIV- exposed but uninfected (HEU) and HIV-unexposed (HU) children. We further hypothesize that biomarkers indicating cardiac fibrosis are upregulated in CAHIV compared to HEU and HU. Our hypotheses are built upon a strong foundation of our own data identifying a high burden of subclinical cardiac dysfunction in CAHIV from a large HIV care program in western Kenya, as well as evidence linking HIV infection to cardiac fibrosis in adults. Upon successful completion of this proposal, we will have uncovered the burden of subclinical cardiac dysfunction in an endemic CAHIV population and identified biomarkers that may be used to test novel methods to identify CAHIV at risk for future cardiac dysfunction. We will test our hypotheses through the following Specific Aims: (1) To determine the extent to which chronic HIV infection is associated with subclinical cardiac dysfunction in CAHIV compared to uninfected children (both HIV-exposed [HEU] and HIV-unexposed [HU]) in an endemic region; (2) to interrogate mechanisms of cardiac dysfunction in CAHIV by determining if blood-based biomarkers related to fibrosis are associated with chronic HIV infection and subclinical cardiac dysfunction; and (3) to determine the prevalence of imaging-based cardiac fibrosis and inflammation in those with perinatal HIV infection compared to uninfected comparators. To complete our Aims, we will conduct a prospective study of a total of 600 CAHIV, HEU and HU in western Kenya and obtain echocardiograms, a clinical assessment and biospecimens. Outcome measures are abnormal myocardial performance index, global longitudinal strain, levels of galectin-3 and other biomarkers. For Aim 3, we will enroll 60 perinatally HIV-infected individuals and 60 uninfected comparators from the US, using cardiac magnetic resonance imaging to compare the extent of cardiac inflammation and fibrosis. Our scientific contribution is expected to be significant because we are addressing a dire health comorbidity for CAHIV with deep clinical, imaging and biomarker phenotyping in an endemic population. As a consequence of the work proposed, we expect to uncover novel insigh...