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

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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.