Summary Numerous recent studies have revealed the significant interplay between microbiota and mammalian host. This interaction appears to play a role both in how the immune system develops and responds to antigens and pathogens and in shaping some disease states. In this application, we propose experiments that investigate how perturbation of the GI microbiome in the setting of vaccination with SIV recombinant live attenuated oral poliovirus affects the immunity stimulated by the vaccine and its efficacy on protection from SIV transmission and disease. Correlations between different GI microbiota compositions and vaccination outcomes will be attempted. To accomplish these goals, the specific aims of this proposal are: to determine if the oral administration of a vaccine including SIV-OPV alters the RM GI microbiota, to evaluate the immune responses stimulated by this vaccine, and whether SIV infection modulates the GI microbiota differently in the presence of preexisting immunity; to investigate whether the innate and adaptive immune responses to SIV vary when vaccination occurs in the presence of a GI microbiota perturbed by antibiotic treatment, and whether there are correlations between microbiota composition and stimulated SIV immune responses that provide protection from SIV infection and AIDS; to explore mechanistic correlations between different GI microbiota and vaccine-induced anti-SIV immune responses by integrating SIV immunity data with system biology data descriptive of colon mucosa gene expression at different time points during the trial.