Latent reservoir characterization and correlations with neurocognitive functioning and thymic output over 12 years in HIV-infected children given early antiretroviral treatment in South Africa Children who participated in the Children with HIV Early Antiretroviral (CHER) Trial in Cape Town are the main population in this application. The CHER trial took place in Cape Town (1/3) and Soweto (2/3) between June 2005 and September 2011. In this study, 377 infants below 12 weeks of age were randomized at a median of 7 weeks of age to deferred antiretroviral therapy (ART) according to 2006 guidelines (ART-Def), or immediate primary ART until either Week 40 (ART-40W) or Week 96 (ART-96W). Thereafter, ART was discontinued until criteria (CD4 <20% or CDC Stage C or severe Stage B) for re-initiating ART developed. Throughout the CHER study, peripheral blood mononuclear cells (PBMCs) were collected every 3 months and stored in liquid Nitrogen. In ART-Def, median age of starting ART was 6 months. In Cape Town, 24 of 80 children randomized to early ART did not interrupt because of already having CDC C or severe Stage B disease, thus were on continuous ART from 7 weeks of age. Children from Cape Town participated in a neurodevelopmental sub-study and are now enrolled in an ongoing study describing neurocognitive functioning and neuroradiological findings for the next 3 years. Using stored samples from the CHER trial from both study sites, studies of thymic outflow (TREC etc) and also HIV reservoir are in progress using stored PBMCs. For the reservoir studies, a PCR for HIV Long Terminal Repeats (LTR) (circular and linear) is being used. This study will address total reservoir size at study exit (Wek 240) in all children with plasma HIV RNA below 400 copies/mm3 and also reservoir size in 20 children from each study arm;in ART-Def at weeks 96, 150 and 200;in ART-40W at week 40, at restarting ART and week 200 and in ART-96W at week, 96, at restarting ART and at Week 200. Through this application, we plan more detailed studies of early stored PBMC specimens from Cape Town CHER patients. As the median age of children is now 7 years of age, we plan prospective studies to further characterize the reservoir, being able to safely collect larger bloo volumes for infectivity assays and to characterize how the reservoir will decay over time. We will correlate reservoir size with neurocognitive/ neuroimaging outcome and thymic outflow in our cohort. A new cohort of HIV-infected infants initiated on ART within the first week of life will alo be studied.
We aim to recruit 12 subjects per year, and will compare reservoir size in these infants with results from the CHER subjects, who were started at a median of 7 weeks of age. As the cure agenda expands and new modalities to purge the HIV reservoir become feasible, our cohort will be well placed for interventional studies.

Public Health Relevance

and Public Health Relevance Findings from the Children with HIV Early Antiretroviral (CHER) trial of early antiretroviral therapy (ART) on South African infants confirm the benefits of early treatment, shaping international guidelines for treating pediatric HIV. This research will build on this pivotal work by studying HIV reservoirs stll present and how the reservoirs change over time, contributing to the long-term goal of cure.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZHD1-DSR-A (50))
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Brouwers, Pim
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Stellenbosch University Tygerberg Campus
South Africa
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