Pre-term birth (PTB) is a major cause of neonatal mortality worldwide, associated with high morbidity due to infectious and other complications. Identifying risk factors for adverse birth outcomes, as well as the likely causes, will facilitate prevention measures to mitigate these outcomes. Sub-Saharan Africa (SSA) has the highest burden of these adverse pregnancy outcomes, and also bears the brunt of the global HIV epidemic, with over 33 million people living with HIV. Untreated maternal HIV infection has been shown to be associated with spontaneous PTB in some but not all studies. Antiretroviral (ARV) drug treatment during pregnancy dramatically reduces perinatal HIV transmission but has also been linked to adverse birth outcomes. Here, we will utilize our completed and ongoing cohorts of pregnant women in Cape Town, South Africa, and build on our previous phase 1 NIH-SAMRC funding (R21 HD083344), to study the impact of HIV/ARV exposure on female genital tract microbiology and metabolome and the relationship with placental immune pathways that impact infant health: prematurity and post-partum vaccine immunogenicity.
The specific aims are 1) To identify vaginal microbial and metabolic markers for adverse birth outcomes in HIV-infected women. Here, we hypothesis that PTB is associated with specific vaginal microbial communities leading to alterations in metabolic pathways that can result in cell stress and subsequent placental inflammation. We will use 16S rRNA sequencing and unbiased mass spectrometry to measure vaginal microflora and metabolites during gestation. 2) To interrogate immune cell subsets and gene expression pathways in placental decidual and villous tissue which lead to PTB in HIV-infected pregnancies. We hypothesize that placental T cells are skewed away from regulatory towards inflammatory and activated states through HIV/ARV exposure, leading to increased risk of preterm labor. We will use a combination of multiparameter flow cytometry, imaging and RNAseq to characterize T cell populations, their tissue location and function. Placentas from HIV-uninfected women will be used as controls. 3) To identify decidual immune cells and gene expression pathways that influence infant cellular immunity. We hypothesize that inflammatory conditions at the fetal-maternal interface contribute to the development of compromised vaccine-specific immunity post-partum. We will measure infant BCG T cell responses in the first two months of life and relate this to placental cell phenotype, function and gene expression in mother-infant pairs. Identifying risk factors for adverse birth outcomes, as well as the likely causes, will facilitate prevention measures to mitigate these outcomes. ! !
HIV-infected, antiretroviral-treated women are more likely to have adverse birth outcomes, and their infants have altered immunity even in the absence of HIV-infection. Here, we will investigate the impact of maternal vaginal microbiome and metabolites during pregnancy and immune regulation and inflammation in placentas at delivery on preterm birth risk in HIV-infected women. We will utilize a long-standing cohort study population in Cape Town South Africa to determine which immune events at the fetal-maternal interface contribute to spontaneous preterm birth in HIV infection, and whether these relate to impaired newborn immunity.