Investigating the Impact of In Utero HIV or Malaria Exposure on CD4+ T Cell Development
Pregnancy-associated malaria, including placental malaria (PM), causes ~100,000 infant deaths per year and maternal HIV infection significantly increases the risk of severe infant morbidity and mortality. Epidemiological studies have reported that children born to mothers with PM have an increased susceptibility to malaria infection. In addition, children born to HIV positive mothers, even those on anti-retroviral therapy (ART), are more prone to severe PM and develop poor vaccine responses. Collectively, these epidemiological studies suggest that in utero HIV or malaria exposure may hamper the development and/or induce dysfunction of immunity in infants. Recent work has suggested that in utero antigen exposure leads to the preferential development of regulatory T cells (Tregs) that may suppress effector T cell responses. However, the impact of in utero HIV or malaria exposure on T cell development remains largely unknown. Determining how in utero antigen exposure impacts the development of T cell immune responses may provide the foundation for understanding suboptimal immune responses to HIV and malaria. The proposed study will leverage cord blood samples from an ongoing program project grant of 500 HIV-infected and uninfected mother-child pairs in a malaria endemic setting in Uganda To test the hypothesis that in utero exposure to HIV or malaria alters CD4+ T helper subset development, we will assess CD4+ T helper cell frequency, activation, phenotype and function in cord blood samples from mothers who are 1) HIV+PM- vs. HIV- PM- and 2) HIV- PM+ vs. HIV- PM-. Statistical analyses will utilize STATA software and groups will be compared using the Wilcoxin rank sum test. The results of this study will provide a better understanding of how early-life exposures to HIV and/or malaria may alter immune development. Importantly, these findings may inform the mechanisms of immune dysfunction during HIV and malaria, ultimately influencing the design and implementation of successful HIV and malaria vaccines.