Microbiome-driven immune changes and growth stunting in HIV-exposed uninfected children

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PROJECT SUMMARY Despite increasing access to antiretroviral therapy (ART) in pregnancy, the >1 million children born annually to pregnant people with HIV (PPHIV) who are HIV-exposed but uninfected (HEU) remain at >2-fold higher risk of growth stunting and infectious morbidity than HIV-unexposed children. Though the origins of adverse HEU child health outcomes are poorly understood, mounting evidence suggests that abnormal microbiome development may play a key role. However, the mechanisms remain elusive, and a better mechanistic understanding is essential to improve care. Our overarching goals are to identify clinical, environmental, diet, and epidemiologic features associated with growth stunting in HEU children, characterize mechanisms of host-microbe communication, and link gut microbiome profiles to immune development in growth stunted HEU children using a multi’omics approach. To do so, we will leverage data, biobanked, and newly collected samples from an ongoing prospective longitudinal birth cohort in Uganda to relate growth stunting, diarrheal disease burden, and adverse clinical outcomes to microbiome-driven changes in HEU child immunity. Innovation: Our disease model examining and characterizing relationships between transferred maternal immunity, child gut microbiome and immune profile development, and childhood growth stunting is novel, highly relevant, and conceptually innovative. Distinct advantages of our proposed research include 1) simultaneous comparison of samples from HIV-exposed and -unexposed groups to minimize confounding, 2) rich clinical, epidemiologic, and environmental exposure data in a well-characterized longitudinal cohort, 3) integrated multi’omics approach leveraging metagenomics, metabolomics, and immun’omics, to identify novel mechanisms of growth stunting and immune development. Investigators: Our interdisciplinary team with expertise in epidemiology, birth cohorts and infectious diseases (Bebell); immunology (Alter, Bernshtein), multi’omics (Mehta, Chan, Huttenhower) is well-poised to complete this work. Approach: We will leverage biobanked samples and extend follow-up of enrolled mother-child dyads in Dr. Bebell’s (K23AI138856) birth cohort, Dr. Bernstein’s adaptations of the Systems Serology platform to enteric organisms, and Dr. Mehta’s established multi’omics laboratory and data pipeline infrastructure to elucidate the effects of maternal HIV exposure and microbiome composition on child growth and immune development through age 5 via these Specific Aims: 1) Identify clinical metadata features associated with growth stunting in HEU children with fine resolution; 2) Characterize gut microbiome features associated with growth stunting in HEU children and establish mechanisms of host-microbe communication using metabolomics; 3) Define alterations in transplacental antibody transfer and breast milk antibody composition specific to pathogenic and non-pathogenic gut organisms in PPHIV and growth-stunted HEU children. Identifying HIV-related microbiome abnormalities and immune mechanisms of growth faltering has great potential to improve child health outcomes by informing vaccine strategies, microbiome therapy, and early intervention for children at high risk of poor growth outcomes.