Persistence of HIV-specific B cells after long-term antiretroviral therapy in early treated Thai children

About This Grant

PROJECT SUMMARY Early initiation of antiretroviral therapy (ART) after perinatal HIV infection is critical to reduce morbidity and mortality, while also limiting seeding of the HIV reservoir. However, while infants develop broad neutralizing antibodies in the absence of ART, early initiation of ART blunts the HIV-specific humoral immune responses in children. We have found that children enrolled in the Thai HIV-NAT209 cohort had limited development of HIV- specific IgG antibodies but, intriguingly, had increasing levels of HIV-specific IgM antibodies through the first three years of suppressive ART. This cohort provides a unique opportunity to study the early HIV-specific humoral response through characterization of IgM antibodies and germline-like IgM+ non-class-switched memory B cells. Through additional analysis of samples from children who experienced a period of viremia after ART initiation and developed HIV-specific IgG responses, we can characterize the differentiation of the humoral immune response after further antigen exposure. It has been shown that adults who initiated ART during acute HIV infection and later experienced a period of viremia developed neutralizing antibodies, and we hypothesize that children will similarly develop neutralizing antibodies after viral non-suppression. Further, we hypothesize that children will have distinct HIV-specific humoral immune characteristics compared to adults who initiated ART in acute HIV infection, including higher frequencies of HIV-specific non-class-switched memory B cells, shorter heavy chain complementarity-determining region 3 (HCDR3) lengths and lower levels of somatic hypermutation in the HIV-specific B cell receptor repertoire, and neutralizing antibodies with broader epitope targeting. To address this hypothesis, we will: (1) determine the magnitude, neutralization capacity, and epitope targeting of HIV-specific IgM and IgG antibodies and (2) determine the B cell receptor repertoire and transcriptome of HIV- specific B cells in children and adults who initiated early ART and either remained suppressed or experienced a period of viremia after ART initiation. Data from these studies will provide important information about the IgM+ HIV-specific humoral responses that persist in early treated children and their development of neutralizing antibody responses after antigen re-exposure, and will help to inform the development of pediatric targeted HIV vaccines to promote development of broadly neutralizing antibodies.