Influence of maternal virome and HIV status on infant gut virome, growth and immunity

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PROJECT SUMMARY/ABSTRACT The early life microbiome plays a significant role in health and disease, including immune development and maturation. Maternal microbiota is a major determinant of infant microbiota. Studies investigating maternal- infant microbiota transmission and its consequent influence on infant immunity have focused on the bacterial component. Yet the impact of maternal virome on infant virome is largely unknown, and studies of the virome in early life are limited. Infants born to mothers living with HIV are more vulnerable to diseases, have stunted growth, and have altered immunity, including immune activation, even when they are not infected with HIV themselves. Much work has gone into understanding the reasons for this phenomenon. Given that the enteric virome is expanded in HIV infection, it is not surprising that our preliminary data show that infants born to HIV- infected mothers inherit a wider range of viruses than unexposed infants. Thus, similarly to the bacterial microbiome, the gut virome could also play an important role in modulating immune responsiveness and growth of infants. We hypothesize that the infant enteric virome is vertically transferred, and the expanded enteric virome of infants born to mothers who are HIV-infected leads to accelerated immune ontogeny and activation, which influences the morbidity of infants exposed to HIV. We propose to: 1: Determine the influence of maternal virome on the infant enteric virome and compare the virome succession in infants exposed and unexposed to HIV through the first 9 months of life. The viromes of matched mother- infant pairs will be determined via metagenomic sequencing of nucleic acid isolated from purified viral particles. Maternal fecal and vaginal virome composition will be correlated with that of the infants’ gut in the first week postpartum. The composition of the enteric virome will be compared between infants exposed and unexposed to HIV during the first week, 4, 15 and 36 weeks of life. 2: Evaluate the relationship between the virome and the bacterial microbiota in infant stool. We will assess the relationship between bacteriophage and their bacterial targets longitudinally. 3: Evaluate the relationship between the infant enteric virome and intestinal inflammation, immune ontogeny and linear growth. To test the hypothesis that the expanded enteric virome in uninfected infants exposed to HIV contributes to greater immune diversity in early life, we will longitudinally assess circulating NK and T cell ontogeny using CyTOF analysis over the first 9 months of life. To test whether the virome causes altered immune ontogeny, we will feed infant mice with phages with and without their bacterial hosts and evaluate the effect on immunity. Understanding the factors that shape the infant gut virome and its consequent impact on bacterial microbiota, immune ontogeny and linear growth could facilitate the development of interventions to reduce infant morbidity and mortality, particularly for those who are exposed to HIV.