The Maternal Immune Legacy of In Utero HIV Exposure

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PROJECT SUMMARY Nearly 1.3 million infants who are HIV-exposed but uninfected (iHEU) are born each year. Maternal HIV infection has a profound and long-lasting impact on the cellular immunity of iHEU through as yet unexplained mechanisms. Maternal microchimerism (MMc) refers to the transfer of rare maternal cells to the fetus during pregnancy which may persist for decades after birth. In offspring of healthy pregnancies at birth, these maternal cells are present in many different immune subsets with the highest level in antigen experienced T-cells; however, the impact of these cells on infant immunity is unexplored. Infant T-cell immunity maybe restricted during early life, so inherited maternal cellular immunity may play a crucial role in response to infection in the offspring. In a cohort from South Africa, we have found that MMc is easily detectable in both iHEU and infants unexposed to HIV (iHU) across the first year of life. It is unknown whether the cell type, diversity, or antigen-specificity of these maternal cells varies between iHEU and iHU. Adults living with HIV have an increased CD8 to CD4 T-cell ratio and a markedly restricted T-cell receptor (TCR) repertoire, and we and others have observed CD8 T-cell infiltration into the placentas of pregnant women living with HIV. Based on these observations, we hypothesize that the maternal T-cells acquired by iHEU are shifted toward CD8 T-cells with a restricted TCR repertoire, as compared to those acquired by iHU. Further, we have observed that some iHEU and iHU exhibit a 50-fold increase in MMc at 15 and 36 weeks of life, such that up to 1 in 200 white blood cells appears to be maternal. This expansion provides us an opportunity to evaluate the TCR repertoire under conditions that likely reflect a new immune stimulation. At the time of these expansions the infants are well and have not recently been vaccinated, so these expansions may result from newly acquired infections. For example, more than half of African infants are infected with cytomegalovirus (CMV) in the first six months of life, and infection is often asymptomatic. We expect that the mothers of these infants will be ubiquitously CMV infected, with 10-30% of memory CD8 T-cells CMV-dedicated. We therefore hypothesize that these large increases in MMc reflect maternal CMV-specific T-cells which expand during acute CMV infection in the infant. Using peripheral blood mononuclear cells from the same cohort, we now propose to investigate the distribution and diversity of maternal T-cells acquired by iHEU and iHU. We further propose to investigate the functional capacity of maternal CMV-specific memory T-cells by determining whether they proliferate in response to acute CMV infection in the infant. We anticipate that this study will demonstrate that inherited maternal cellular immunity plays an important role in responding to infection during infancy with a differing effect in iHEU and iHU. Such an observation would have profound implications for the study of infant immunity, vaccination, and infectious disease susceptibility. We propose a novel model in which the immune responses observed during infancy are the product of two, rather than one, immune systems.