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HIV's primary site of infection is at mucosal surfaces. To successfully defend against sexually transmitted diseases (STDs), including HIV, protection may need to be specifically elicited at the mucosal interface, where the organism enters the host. Recent advances in measuring adaptive responses at mucosal sites and optimization of techniques for low-dose repeated mucosal challenge in nonhuman primate animal models allow more in depth studies of mucosal vaccine vectors.Although parenterally administered vaccines can elicit responses at mucosal sites, vaccination of mucosal sites is being explored in an attempt to increase the frequency, strength and distribution of the adaptive mucosal response. Recent studies in nonhuman primates involve vaccination of the gastrointestinal tract and rectum, as well as the nose, oropharynx or respiratory tree in an attempt to elicit responses at the distal mucosal sites where HIV transmission occurs, the rectum and genital tract.Recent experiments in nonhuman primates indicate that vaccination at mucosal sites can elicit robust responses in the periphery and at mucosal sites, although the response pattern varies widely by route and regimen used. For most regimens, disease course after challenge did not differ by route of vaccination.