# Gut Microbiota and Other Factors Associated With Increased Regulatory T Cells in Hiv-exposed Uninfected Infants

## TL;DR

HIV-exposed uninfected infants have higher regulatory T cells, possibly due to gut microbiome changes and other factors, which may weaken their immune defenses.

## Contribution

Identifies maternal and infant gut microbiome dysbiosis as a key driver of increased regulatory T cells in HIV-exposed uninfected infants.

## Key findings

- At birth, HEU infants had higher frequencies of certain Treg subsets compared to HUU infants.
- Differential gut microbiome composition in mothers and infants correlated with Treg subset frequencies in HEU infants.
- In vitro experiments confirmed that bacterial taxa from HEU infants expanded Treg subsets observed in vivo.

## Abstract

HIV-exposed uninfected infants (HEU) have higher infectious morbidity than HIV-unexposed infants (HUU). HEU have multiple immune defects of unknown origin. We hypothesized that HEU have higher regulatory T cells (Treg) than HUU, which may dampen their immune defenses against pathogens. We compared 25 Treg subsets between HEU and HUU and sought the factors that may affect Treg frequencies. At birth, 3 Treg subsets, including CD4 + FOXP3 + and CD4 + FOXP3 + CD25+, had higher frequencies in 123 HEU than 117 HUU and 3 subsets were higher in HUU. At 28 and 62 weeks of life, 5 Treg subsets were higher in HEU, and none were higher in HUU. The frequencies of the discrepant Treg subsets correlated at birth with differential abundances of bacterial taxas in maternal gut microbiome and at subsequent visits in infant gut microbiomes. In vitro, bacterial taxa most abundant in HEU expanded Treg subsets with higher frequencies in HEU, recapitulating the in vivo observations. Other factors that correlated with increased Treg were low maternal CD4 + T cells in HEU at birth and male sex in HUU at 28 weeks. We conclude that maternal and infant gut dysbiosis are central to the Treg increase in HEU and may be targeted by mitigating interventions.