Evaluating predictors and neuropsychological outcomes associated with biomarkers of biological age in children and adolescents with perinatally acquired HIV

About This Grant

PROJECT SUMMARY The goal of this project is to evaluate telomere length (TL) and epigenetic age (EA), important biomarkers of biological age, in children with perinatally acquired HIV (CPHIV), children who were HIV exposed and uninfected (CHEU), and children who were HIV unexposed and uninfected (CHUU). CPHIV grow into adulthood on effective, lifelong antiretroviral therapy (ART); however, adults with perinatally acquired HIV are at higher risk of chronic health issues. There is evidence that adults with HIV have shorter TL and accelerated EA compared to adults without HIV, but this association is not as clear in pediatric populations. TL and EA have been associated with adverse health outcomes and all-cause mortality. Childhood is a sensitive time for changes to TL and EA. TL decline and EA acceleration are not well characterized in children, and leveraging longitudinal samples to evaluate these biomarkers of biological age in CPHIV – who are higher risk of future adverse age-related morbidities – could inform strategies to improve long-term health outcomes. To better understand biological age in CPHIV, we plan to compare TL decline and EA among CPHIV, CHEU, and CHUU, compare TL decline and EA acceleration between CPHIV who initiated ART early versus later, determine predictors of TL decline and EA acceleration, and evaluate the association between biomarkers of biological age and neuropsychological outcomes. This project will leverage samples and survey data from three unique cohorts enrolled in ongoing studies (R33HD103079, PI: Dr. Grace John-Stewart and R01HD023412, MPI: Grace John-Stewart, Dalton Wamalwa). Two of the parent cohorts have followed CPHIV for over 15 years, which will allow for robust longitudinal analyses of TL decline and EA acceleration. Aim 1 will compare TL decline from infancy through 24 months and EA at 24 months of age among CPHIV, CHEU, and CHUU using linear mixed effects models. In Aim 1, we will also use hierarchical clustering to identify clusters of children with similar biological aging profiles at 24 months and multinomial logistic regression to determine cluster differences among CPHIV, CHEU, and CHUU. Aim 2a will leverage repeated samples collected at 4 and 16 years of age to compare long-term TL decline and EA acceleration between CPHIV who started ART within the first year of life and CPHIV who started ART later. Aim 2b will determine correlates of TL decline and EA acceleration among CPHIV. Correlates evaluated include levels of total and intact HIV DNA, HIV viral load, cytomegalovirus viral load, and interleukin- 6. Aim 3 will determine the association between biomarkers of biological age and neuropsychological outcomes among children in long-term follow up at 7 and 16 years of age. Findings from this project will address gaps and in knowledge of biomarkers of biological age. This research plan will provide the K01 candidate with rigorous training focused on biomarkers of biological age and HIV, machine learning techniques, neuropsychological outcomes of children and adolescents with HIV, and community engagement and equitable partnerships to support her independence.