Uncovering the Biological Link between Oral and Mental health in Adolescents Living with HIV (uBLOoM)

PROJECT SUMMARY With the global scale-up of antiretroviral therapy (ART), increasing numbers of children with perinatally-acquired HIV (PHIV) are surviving into adolescence and beyond. Adults living with HIV on ART are at an increased risk for chronic age-related illnesses, including neurocognitive impairment, as well as oral disease compared to the general population. Early precursors of these disorders are also highly prevalent in children and adolescents living with HIV (ALHIV). Given that mental and oral health co-morbidities associated with HIV and lifelong ART could be driven by overlapping or distinct biological and immunological mechanisms, a better understanding of these mechanisms is needed to support interventions, particularly among ALHIV. Microbiota- or aging-mediated processes have been shown to contribute directly to HIV comorbidities. Increased incidence and prevalence of dental pathologies observed by our group and others among people living with HIV appears predicated by a differential colonization with pathogenic and commensal microbes. Emerging evidence suggests that controlled HIV infection alters microbial communities, contributing to a chronic low-grade inflammatory state that underlies age-associated conditions in children and youth with PHIV. In parallel, epigenetic age acceleration is observed in adults with HIV on ART when compared to controls and has been linked to neurocognitive deficits. The objective of this proposal is to identify oral microbial taxonomic and functional features, and aging markers associated with neurocognition and oral health in ALHIV. Our multidisciplinary research team is comprised of experts in HIV epidemiology, microbiology, dentistry, medicine, pediatrics, neuropsychology, bioinformatics and statistical modeling. We will leverage an established NIH-funded cohort of approximately 600 children and adolescents perinatally exposed (+/- PHIV) and unexposed (controls) to HIV living in Nigeria. In 50 ALHIV and 50 sex- and age-matched uninfected adolescents (aged 10-13), we will analyze shotgun metagenomic sequences of salivary samples to identify salivary taxonomic and functional profiles and will use the comprehensive Illumina MethylationEPIC BeadChip array to characterize DNA methylation and measure markers of epigenetic age acceleration in blood samples. In Aim 1, we will characterize shotgun metabolic sequences of salivary samples and measures of epigenetic age acceleration in blood samples to examine associations between (a) oral microbial and functional profiles and (b) epigenetic age acceleration with neurocognition outcomes in Nigerian adolescents with and without HIV. In Aim 2, we will test whether epigenetic age acceleration is associated with oral health outcomes in Nigerian adolescents with and without HIV. The research proposed in this R01 is significant because it will generate new insights into how microbiota- or aging- mediated mechanisms contribute to neurocognitive impairments and oral conditions in ALHIV.