DESCRIPTION (provided by applicant): In a recent survey in South Africa, 95% of HIV-positive pregnant women received antiretroviral therapy (ART), and 68% of HIV-exposed infants received ART. Among the estimated 330,000 HIV-infected children in South Africa, 58% receive ART. Research suggests that there are long-term effects associated with in utero exposure to HIV and ART, warranting further study of this burgeoning population of HIV-exposed uninfected (HEU) children. In particular, very little is known about the long-term effects of HIV infection an ART treatment on brain development in pediatric populations, which we will investigate in the proposed study. We have access to an on-going longitudinal neuroimaging study combining several complementary, non-invasive magnetic resonance imaging (MRI) data sets with clinical and neuropsychological measures. The existing study (funded from R21 MH096559 and R01 HD071664) has been following a cohort of children carefully monitored since birth as part of the "Children with HIV early antiretroviral therapy" (CHER) trial (part of Comprehensive International Program for Research in AIDS (CIPRA-SA), sponsored by the Division of AIDS, National Institute of Allergy and Infectious Diseases). At 7 weeks, HIV-infected children were randomly assigned to either one of two early ART arms or to a deferred ART arm. In the cohort, the HIV-uninfected control group includes both HIV-unexposed, uninfected (HUU) and HEU children. At 5 and 7 years, children received clinical, neuropsychological and neuroimaging (structural, diffusion and spectroscopic; resting state functional MRI (RS-FMRI) at 7 years only) assessment. At 9 years (beginning June 2014), the same multimodal imaging and evaluations will be repeated. This project seeks to expand the current neuroimaging measures (under the existing R01) to include MR spectroscopic lactate and lipid concentrations, and to develop new multimodal markers involving brain network connectivity measures. We hypothesize that these additional multimodal biomarkers will be sensitive to the effects of HIV infection, timing and long-term usage of ART, and in utero ART/HIV exposure on brain development. This project extends the existing collaboration between Drs Meintjes (University of Cape Town), Laughton (Stellenbosch University), and van der Kouwe (Massachusetts General Hospital) to include Dr Bharat Biswal from New Jersey Institute of Technology (NJIT) who is a leading authority on RS-FMRI analyses, as well as two UCT-based early stage investigators, Drs Holmes and Taylor.

PUBLIC HEALTH RELEVANCE: A South African cohort including both HIV-exposed uninfected children and HIV-infected children receiving antiretroviral therapy (ART) since infancy has been closely monitored using several noninvasive neuroimaging modalities, clinical examination and neuropsychological testing at ages 5, 7 and 9 years as part of an ongoing study of long-term effects of both HIV and ART on brain development. We will strengthen existing collaborations between the New Jersey Institute of Technology, University of Cape Town, Stellenbosch University and Massachusetts General Hospital in order to develop novel multimodal biomarkers of HIV- and ART-associated neurological effects, based on assessments of functional networks, structural connections and underlying metabolite measures (with data from the latter expanded as part of this application). This study will be used to further understand the effects of HIV infection as well as long-term usage and in utero exposure of ART on brain development, and the results may be useful in informing health policy related to the ideal management of HIV in children as well as determining the ideal combination of ART treatments for HIV-positive pregnant women and HIV-infected children.