Breastfeeding can account for up to 39% of pediatric HIV infections. In developed countries, HIV-infected mothers feed formula to their infants to prevent postpartum HIV transmission. However, in many parts of the developing world, formula is unaffordable and is associated with high morbidity and mortality due to infectious diseases such as gastroenteritis and malnourishment. Therefore, the current WHO guidelines recommend that HIV-infected mothers from most underdeveloped settings breastfeed their infants. Multiple observational, prospective studies have shown that exclusive breastfeeding (EBF) reduces the risk of mother-to-child- transmission (MTCT) two to tenfold compared to infants that are mixed-fed (MF) with other milks, liquids, or solids in addition to breast. EBF decreases morbidity even in non-HIV-exposed infants in both developed and developing settings. EBF decreases morbidity even in non-HIV-exposed infants in both developed and developing settings. However, EBF is difficult for mothers to maintain, and infants are given complementary foods after four to six months of age. In addition, a study of EBF with rapid weaning at four months showed high morbidity in the uninfected infants. Understanding the mechanisms associated with this increased risk could lead to interventions to make mixed feeding and complementary feeding safer for infants. One potential explanation for the protective effect of EBF is that the addition of non-breast milk liquids and solids alters the infant's mucosal or immunologic barriers of the upper gastrointestinal tract. This could lead to immune cell activation with an increase HIV target cells at the mucosa, or increased microbial translocation across the gut, possibly due to compromised mucosal integrity or increased gastrointestinal and/or systemic infections. This project tests the hypothesis that mixed fed infants will display evidence for immune activation within both mucosal and systemic compartments when compared to EBF infants (Aim 1), by measuring immune activation in the blood and in saliva of infants with different feeding practices. This increase in immune activation could be due to changes in the gut commensal organisms in early life (Aim 2). Therefore, these experiments will analyze the microbes in stool of these babies. This activation is possibly derived from mixed feeding- induced mucosal impairment or infections and the consequent translocation of bacterial products across the gut mucosa into the systemic circulation (Aim 3), therefore our experiments will measure microbial products in blood. Through assessment of these infants at multiple time points (6 and 14 weeks of age), this study plans to evaluate the mechanisms conferring EBF infants a reduced risk of HIV infection, and to uncover targets for MTCT prevention during mixed feeding, and to potentially benefit all infants globally who cannot EBF.

Public Health Relevance

These studies are designed to mechanistically discern why HIV transmission is increased in mixed fed infants. These data have the potential to lead to future studies of interventions to prevent postpartum MTCT, such as specific immune interventions to down-modulate the numbers of target cells or through targeted gut microbial therapies through the use of probiotic supplementation for mixed fed infants.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HD069201-03
Application #
8452696
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Raiten, Daniel J
Project Start
2011-04-01
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
3
Fiscal Year
2013
Total Cost
$128,835
Indirect Cost
$9,047
Name
Seattle Biomedical Research Institute
Department
Type
DUNS #
070967955
City
Seattle
State
WA
Country
United States
Zip Code
98109
Kidzeru, Elvis B; Hesseling, Anneke C; Passmore, Jo-Ann S et al. (2014) In-utero exposure to maternal HIV infection alters T-cell immune responses to vaccination in HIV-uninfected infants. AIDS 28:1421-30
Gervassi, Ana; Lejarcegui, Nicholas; Dross, Sandra et al. (2014) Myeloid derived suppressor cells are present at high frequency in neonates and suppress in vitro T cell responses. PLoS One 9:e107816
Wood, Lianna F; Chahroudi, Ann; Chen, Hui-Ling et al. (2013) The oral mucosa immune environment and oral transmission of HIV/SIV. Immunol Rev 254:34-53
Jaspan, Heather (2011) The wrong place at the wrong time: geographic disparities in young people's HIV Risk. J Adolesc Health 49:227-9