# Influence of breast milk immunoglobulins on gut microbiota and immune development in infants exposed to HIV

> **NIH NIH R21** · SEATTLE CHILDREN'S HOSPITAL · 2022 · $188,500

## Abstract

While the number of new pediatric HIV infections has been drastically reduced, this has led to an increasing
population of infants who are HIV-exposed but uninfected (iHEU). iHEU have been shown to have altered
immunity and gut bacterial communities. However, the mechanisms behind these phenotypes in iHEU are not
well understood. Human breast milk is key in transferring antibodies to protect the baby against infections;
especially early in life when their immune system is still immature. Persons living with HIV have been shown to
have an abnormal B cell compartment which leads to polyclonal antibody binding compared to uninfected people.
Also, HIV infected people have higher concentrations of IgG1 and IgG3 and reduced IgG2 in their serum versus
controls. Interestingly, IgG2 and not IgG1 has been shown to be involved in commensal targeting in humans and
is known to be less inflammatory and involved in T-independent responses. It is not clear whether the
immunoglobulin isotypes and subclass distribution differs in the breast milk of women living with HIV (WLWHIV).
Similarly, whether the distribution of immunoglobulin subclasses in breast milk of WLWHIV are transferred to
their infants is unknown. Moreover, maternal antibodies have been shown to bind to commensal bacteria in the
newborn gut and lead to dampening of the immune system in mouse models. These antibody-microbe
interactions were shown to differ depending on the antibody subclass. For example, while IgG2b and IgG3 were
able to bind to commensals, they did not bind to pathogenic bacteria while only minimal binding was observed
for IgG1 and IgG2c in the gut, suggesting functional differences in terms of antigen recognition. Whether a similar
phenomenon occurs in human infants and how the binding will differ in the context of HIV is unknown. The
antibody-microbe binding impacted translocation of bacterial products from the gut into the blood and reduced
dampened T cell activation in murine pups. Similar interactions have been shown to reduce systemic
inflammation in human patients with IgG and IgA deficiencies. Whether antibody-microbe interaction in iHEU
associate with systemic inflammation and immune activation is unexplored.
We hypothesize that HIV infection alters the quantity and subclass distribution of total antibody in breast
milk thereby impacting the antibody-microbe binding profile in the infant gut due to altered transfer of
antibody. This in turn shapes infant gut microbiota resulting in increased immune activation in infants.
We will test these hypotheses with the following specific aims:
Aim 1: Compare concentrations of immunoglobulin isotypes and subclasses in breast milk of women living with
HIV (WLWHIV) versus uninfected mothers at 4 weeks postpartum.
Aim 2: Compare the immunoglobulin-microbe binding profile of IgG and IgA subclasses in stool of iHEU versus
iHU infants.
Aim 3: Assess the relationship between antibody-microbe binding and immune activation in iHEU.

## Key facts

- **NIH application ID:** 10459554
- **Project number:** 5R21HD106574-02
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Donald Nyangahu
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $188,500
- **Award type:** 5
- **Project period:** 2021-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10459554

## Citation

> US National Institutes of Health, RePORTER application 10459554, Influence of breast milk immunoglobulins on gut microbiota and immune development in infants exposed to HIV (5R21HD106574-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10459554. Licensed CC0.

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