T cell receptor repertoire in Kenyan HIV exposed but uninfected infants at birth: evidence of in utero clonal expansions

Abstract

With the expansion of global strategies to prevent mother to child transmission of HIV, the number of perinatal HIV infections had dropped dramatically. This public health achievement has created a population of HIV exposed but uninfected (HEU) infants with substantially more morbidity and mortality than their HIV unexposed (HU) peers. We hypothesize that in utero exposure to maternal HIV induces a premature activation and expansion of fetal T cells, potentially leading to infant immune dysregulation (Th1 polarization/immune exhaustion) upon exposure to pathogens after birth. We selected pre-ARV era cord blood samples from 17 HEU infants born to viremic Kenyan women and 17 cord blood samples from HIV unexposed infants born to Kenyan women with similar sociodemographics. Next generation technology including addition of unique molecular identifiers was used to generate amplicon libraries for sequencing (MiSeq, Illumina). We calculated the Simpson Diversity Index for the 100 most frequent clones per TRB family. The median Ds for HU cord blood samples was 0.1, representing near maximal diversity of the TCR repertoire. Overall, HEU samples displayed a 30% reduction in diversity compared to the samples from HU infants, indicative of fetal T cell clonal expansion. Of note, the median diversity of Kenyan HEU samples located closer to the diversity of American adult peripheral blood than to the diversity of American cord blood. Although the antigen specificity of these cells is unknown, these results support the hypothesis that HIV exposure in utero stimulates fetal immune responses and point towards the existence of specific features of the immune system of newborn HEU infants which might be linked to their poor morbidity and mortality rates.