Identifying inter-kingdom microbial determinants of altered immunity in HIV exposed infants

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PROJECT ABSTRACT Infants born to HIV-infected mothers are at high risk for HIV acquisition. Additionally, HIV-exposed yet uninfected infants display reduced vaccine responses and increased disease susceptibility compared to unexposed infants. The development of certain T cell subsets, both in the mucosa and systemically, is determined by the presence of specific microbes in the gut and may be important in determining adaptive immunity. However, the gut microbiota of HIV-exposed uninfected (iHEU) infants differs from that of HIV- unexposed (iHU) infants, since their mothers have altered gut microbiota. The gut virome also plays a central role in modulating both the bacterial microbiota and immune response of adults, yet the association between the infant enteric virome and cellular responses to vaccination has not yet been explored. This study proposes that the enteric virome is one of the factors influencing the morbidity of HIV-exposed infants, either by directly altering mucosal immunity or by altering the composition of enteric bacterial communities, as a consequence of bacteriophage or other viral dynamics. This proposal will utilize an already funded, ongoing cohort to longitudinally identify interactions between viruses, bacterial microbiota, and cellular responses to vaccination in 40 iHEU and 40 iHU (Aim 1). Viral metagenome data will be integrated with bacterial community datasets and T cell cytokine responses to BCG vaccination to identify viral and bacterial taxa correlated with BCG responses. The effect of the expanded virome on bacterial microbiota and responses to BCG vaccination will then be assessed for causality in gnotobiotic mouse models (Aim 2). The effect of the expanded iHEU viroem on mucosa and peripheral gene expression will be assayed using single cell RNA sequencing in Aim 3. Integrative analyses will be used to identify interactions between specific bacterial and viral taxa, as well as their associated with BCG responses. Together, these Aims will identify mechanisms of gut dysbiosis in iHEU and reveal potential therapeutics to restore health to this group. Collectively, this proposal will reveal how maternal HIV infection shapes the enteric microbiome and immunity of associated infants.