Sodora, DonaldWood, Lianna Frances2015-09-292015-09-292015Wood_washington_0250E_14920.pdfhttp://hdl.handle.net/1773/34113Thesis (Ph.D.)--University of Washington, 2015Over 250,000 new mother to child transmission (MTCT) events occur each year, and at least 40% of these HIV infections are acquired through breastfeeding. Despite the risk of HIV acquisition via breastfeeding, exclusive breastfeeding of infants born to HIV-infected mothers is recommended by the WHO, since, even in the presence of HIV, breastfeeding results in reduced infant mortality, partly due to immune benefits from passive transfer of antibodies and other bioactive products. Therefore, HIV transmission via breast milk continues to be a major route of infant HIV acquisition. This thesis explores four different exposures in early infancy that can alter immune activation and HIV target cell availability in South African infants born to HIV-infected mothers: 1. introduction of non-breast milk foods early in life, 2. maternal HIV disease progression, 3. oral candidiasis and 4. vaccination to infant immune activation. Findings from this work suggest that all 4 exposures may increase HIV susceptibility by inducing immune activation in HIV target cells. Introduction of non-breast milk foods is associated with an increase in the level and activation state of HIV target cells with a T regulatory phenotype. These cells also may be recruited to the oral mucosa by increased levels of CCL5 and CCL22. Evaluation of two potential mechanisms for this increase in HIV target cell activation and recruitment, exposure to food borne toxins, specifically ochratoxin, and changes in the stool microbiome, demonstrate a potential role for altered gut microbiome, particularly an increase in Prevotella copri, in modulating HIV target cell activation and recruitment to the oral mucosa. This thesis also demonstrates that: 1. As maternal CD4 count declines, a predictor of HIV disease progression, breastfed infants show an increase in T cell activation, suggesting that exposure to maternal HIV or HIV-induced immune activation via breast milk increases immune activation in infants; 2. Exposure to Candida, as occurs in oral candidiasis, a common infection of infants, increases CD4 T cell activation in adults; and 3. Vaccination with BCG, which is administered at birth to most infants around the globe, also can increase HIV target cells in the blood of infant macaques. These studies add substantially to our understanding of environmental exposures that increase HIV susceptibility in South African infants, and suggest possible interventions, including probiotic administration, that may decrease HIV susceptibility in breastfed infants.application/pdfen-USCopyright is held by the individual authors.Breastfeeding; HIV Target Cells; HIV Transmission; Infants; Oral Mucosa; South AfricaImmunologyVirologyMedicinepathobiologyThesis