Defining the contribution of HIV diversity to infant immunity

About This Grant

ABSTRACT Developing an effective HIV vaccine has been remarkably challenging in part because attempts to elicit robust antibody responses to HIV immunogens have largely failed. Thus, intense effort has focused on understanding how humans elicit such responses to HIV infection, which occurs in only a subset of individuals. These responses have been primarily studied in adults living with HIV where broadly neutralizing antibodies (bnAbs) often have high levels of somatic hypermutation (SHM) that takes years to develop. Studies in infants suggest they may hold important keys to understanding how to elicit a broadly neutralizing antibody response. Leveraging samples from the Nairobi Breastfeeding Trial (NBT) conducted before the availability of antiretroviral therapy, we showed that infants develop broad neutralizing antibody responses much more commonly and more rapidly than adults. A similar finding was observed in a second cohort from South Africa, which showed that while only 19% of adults develop a broad response, 75% of children infected as infants develop such responses. We further showed that antibodies isolated from infants with a broad neutralizing antibody response have more limited SHM and are part of a polyclonal response. Here we propose to explore the basis for these unique responses in infants, focusing specifically on whether viral diversity plays a role. We hypothesize that the higher levels of viral replication in infants leads to an accelerated arms race between the virus and the B cell responses, driving the breadth and potency of the antibody response. We will test this hypothesis by deeply sequencing the viral population over time in a cohort of infants and a cohort of adults from the same region, collected over a similar time period. We will examine the relationship between viral diversity metrics and the breadth and potency of the neutralizing antibody response. The proposed comparative analyses of infants and adults are possible because of our long-standing collaborative studies that resulted in archived longitudinal samples collected from both infants and adults prior to the availability of antiretroviral treatment. The proposed study will be the first to examine the role of viral evolution in the unique infant antibody response to HIV and the first to directly compare this process between infants and adults.