Persistence of HIV-specific CD8+ T cell responses after long-term ART in early treated Thai children

PROJECT SUMMARY Early initiation of antiretroviral therapy (ART) in perinatally infected infants diagnosed with HIV helps to reduce morbidity and mortality, but it is not sufficient to eradicate the virus. Children have a unique immune system that does not always respond to infection the same way as adults, and an increased understanding of the HIV-specific

immune responses that persist in children after early ART is needed in order to inform development of immunotherapies that promote ART-free HIV viral control in children. In preliminary studies, we have shown that early initiation of ART before six months of age blunted the HIV- specific adaptive immune responses in children enrolled in the Thai HIV-NAT209 cohort. We were able to detect

HIV-specific CD8+ T cells that persisted in these children as late as four years after ART initiation, but the frequency of CD8+ T cells that produced IFN in response to stimulation with HIV peptides was significantly lower in children compared to adults living with HIV on ART. As neonatal CD8+ T cells have impaired production of

IFN, these standard assays may underestimate the frequency of HIV-specific memory CD8+ T cells differentiated during infancy. We have the unique opportunity to follow-up with children of the HIV-NAT209 cohort to determine if these HIV- specific immune responses persist through 6-10-years of ART, and further characterize their phenotype. We

hypothesize that HIV-specific CD8+ T cells that persist after long-term antiretroviral therapy in children with early treated perinatal HIV will be less differentiated than those in early treated adults on long-term ART. To address this hypothesis, we will: (1) determine the magnitude, phenotype, and functionality of HIV-specific CD8+ T cells

that persist in early treated children after long-term ART and (2) determine the T cell receptor repertoire and transcriptomic differences between HIV-specific CD8+ T cells in early treated children compared to adults after long-term ART. We will use unique functional cell-based assays and single-cell RNA-sequencing to analyze HIV-

specific responses in these children and compare them to HIV-specific responses in early treated adults. Data from these studies will provide important information about the persistence and functionality of HIV- specific CD8+ T cell responses in early treated children, and will help to inform the development of pediatric

targeted therapeutic interventions to promote ART-free viral control in children.