Developing Interventions for Protecting HIV-Exposed Uninfected Infants against Severe Infections

PROJECT SUMMARY Developing Interventions for The Protection of HIV-Exposed Uninfected Infants against Severe Infections HIV-exposed uninfected infants (HEU) have increased risk of severe infections, hospitalizations, and death in the first 1-2-years of life than HIV-unexposed infants (HU). This is likely due to decreased immune responses.

The development of the infant immune system is guided by the gut microbiota, which use metabolites and other products as mediators. The immune system also affects the microbiome in this bidirectional relationship. We will compare the interactions of microbiome and immune responses in HEU and HU with the goal of identifying gut

bacterial taxa and their metabolites responsible for the HEU immune defects that may be modulated with diet. In Aim 1, we will define immunogenomic and metabolomic profiles that explain the immune dysfunctions of HEU in the 1st year life. In 50 HEU and 50 HU at 6, 24 and 48 weeks of life, equally distributed between males and

females, we will measure functional, phenotypic, transcriptomic, and epigenetic profiles and identify the genomic networks underlying the loss of NK and T cell effector function. We will integrate the immunogenomic with plasma metabolomic profiles to identify the metabolites associated with HEU immune dysfunction. We will then confirm

the relationship between immunologic and metabolomic characteristics in vitro. In Aim 2, we will compare the gut microbiome composition and function in HEU and HU and identify bacterial taxa associated with the immunologic and metabolomic abnormalities of HEU. We will further confirm the relationship between microbiota and metabolome in vitro. We will also compare the composition of the respiratory

microbiomes of HEU and HU. The respiratory microbiome may play an important role in the differential severity of respiratory tract infections of HEU and HU. Moreover, the respiratory microbiome is modulated by local and systemic immune responses resulting in a well-established correlation between gut and respiratory microbiota.

In Aim 3, we will perform proof-of-concept studies of maternal and infant dietary interventions to modulate the infant gut microbiome. In the 1st study, we will randomize 24 pregnant people with HIV 1:1 to pasteurized fermented milk (PFM) supplementation during the last month of pregnancy or control. We will assess

acceptability and compliance with the intervention and its effect on the neonatal gut microbiome and metabolome at 2-4 weeks of life. In the 2nd study, we will randomize 24 6-month-old HEU 1:1 to 4-week PFM supplementation or control and evaluate the same outcome measures as above at the end of the intervention.

This highly impactful and innovative study will define the relationship of the infant gut microbiomes with immunogenomic, metabolomic, and respiratory microbiome profiles; will identify bacterial taxa that may increase the vulnerability of HEU to infections through decreased immune functions; and will test the ability to alter the

HEU gut microbiome and metabolome through dietary interventions. Our findings will forge a path to design interventions to improve the HEU immune protection and decrease their risk of severe infections, hospitalizations, and death.