DNA methylation (DNAm), an epigenetic process, is critical for neurodevelopment and for neurologic functioning throughout the lifespan. Aberrations in DNAm result in developmental, neurodegenerative, and psychiatric disorders. We have discovered that HIV+ adults have altered DNAm in both brain and peripheral blood mononuclear cells, resulting in accelerated biological aging. Perinatally HIV-infected (PHIV+) children are at increased risk of neurodevelopmental delay and lasting neurocognitive dysfunction. In this study, we examine the role of DNAm in the neurocognitive development of PHIV+ adolescents, while also considering important psychosocial, medical, virologic, and other factors. The immediate goal of this study is to delineate the complex relationship between these various factors in the pathogenesis of neurocognitive deficits in PHIV+ adolescents. The intermediate goal is to utilize the information gained to develop intervention strategies aimed at improving the lives of PHIV+ children as they progress into adulthood. The long term aim of this study is to develop a biomarker of currently concealed neuropathological processes that result from HIV, so that appropriate interventions can be provided to at-risk youths. This study will consider a host of environmental factors known to impact neurodevelopment, including stress, antiretroviral (ARV) medication use, economic adversity, medical comorbidities, and home/family environment. It will leverage the extant resource of the Cape Town Adolescent Antiretroviral Cohort (CTAAC), thereby maximizing efficiency and cost effectiveness, while minimizing human subjects' burden. The combination of cross sectional and longitudinal aims will allow fast translation of the findings and true characterization of neurodevelopmental and cognitive divergences resulting from epigenetic dysregulation due to HIV. In addition, the genome-wide methylation data generated can be used to enhance other research arms of the CTAAC, maximizing the potential return of investment. We also include a capacity building element by funding a postdoctoral fellow from UCT to be trained in biostatistics by UCLA researchers. This study is possible through the collaboration of two teams: The University of Cape Town team, which is currently carrying out the CTAAC neuro sub-study involving 200 HIV+ and 50 HIV- adolescents with diffusor tensor imaging, comprehensive neuropsychological testing, and assessment of childhood psychosocial factors, will provide all data and biological samples, as well as expertise in neuroimaging and pediatric neuroHIV. The University of California - Los Angeles team, which has extensive expertise in epigenetic biostatistical methods and genomic investigations of neuroHIV will process DNA samples and conduct the statistical analyses.
There are a substantial number of perinatally HIV-infected children in South Africa who are at increased risk of neurobehavioral and neurophysiological abnormalities. Interventions for these children need to be informed by elucidating the biological and environmental determinants of such abnormalities. This study will examine the influence of DNA methylation (an epigenetic process) and important environmental and psychosocial factors on HIV neuropathogenesis, with the goal of developing treatment strategies and identifying potential biomarkers.
| Horvath, Steve; Stein, Dan J; Phillips, Nicole et al. (2018) Perinatally acquired HIV infection accelerates epigenetic aging in South African adolescents. AIDS 32:1465-1474 |
