Worldwide, HIV currently afflicts 34 million people including 3.3 million children. Of these, 5 million and 150,000, respectively, are living with HIV n Asia, the most populated continent (4.2 billion people). With the availability of antiretroviral therapy (ART), child mortality rates are decreasing, but children with HIV continue to cope with HIV as a chronic, highly stigmatized, and transmittable illness. Persistence of HIV despite successful ART is the result of the long-term maintenance of stable reservoirs in long-lived cells. Quantifying the reservoir size and its replicative capacity in early-treated children is necessary to elevate our understanding of HIV latency in children, and in turn, inform interventions for cure With this rationale, we will identify determinants for restricted HIV reservoir size and inducible HIV RNA replication in children treated with ART during infancy. The objective is to identify critical timing of ART onset and duration in children that will result in a favorable reservoir profile, defined as having low to undetectable levels of integrated HIV DNA in peripheral blood mononuclear cells and undetectable levels of inducible HIV RNA upon activation in CD4+ T cells. Our central hypothesis is that early ART initiation (d8 weeks) and long durations of ART (e1 year) will be associated with low reservoir size. We will test the central hypothesis by enrolling 260 children who have initiated ART during the first 6 months of life. This will include older children with long-term viral suppression, and newly infected infants who either commence ART after 4 weeks of age or initiate triple antiretroviral (ARV) prophylaxis at birth (due to being at high risk for HIV infection), and then transition to triple ART when HIV is confirmed. The study will measure direct markers of HIV reservoir size and replicability (integrated HIV DNA and inducible HIV RNA), indirect markers of reservoir size (HIV-specific immune responses), and predictive factors of reservoir size (timing of viral suppression, inflammation and low-level viremia) after ART. We will leverage the strength of existing prevention of mother-to-child transmission and pediatric HIV public health and research networks, and the implementation of the 2013 Thai Ministry of Public Health (MOPH) guideline recommending triple-ARV prophylaxis after birth for high-risk infants and earlier infant diagnosis starting at 1 month of age for all HV-exposed infants. This project has strong support from the Thai MOPH and will have high public health impact. Additionally, the CRF01_AE HIV clade that circulates in Thailand and other Asian countries may be associated with unique immunologic and virologic responses important for HIV persistence, and this study will be among the few to evaluate HIV persistence in Asian children. Our long-term goal is to translate knowledge on the latent reservoir in early-treated children into interventions that will lead to HIV cure.
The proposed work has high public health relevance, as it will fill knowledge gaps in identifying determinants of restricted HIV reservoir size and replicability n children started on antiretroviral therapy during infancy. These outcomes will be critical to the successful design of interventions to achieve HIV cure for children living with HIV.