ART dramatically reduces the viral burden in HIV-1 infected individuals. However, because it fails to eradicate recrudescing viremia, life-time administration, which is associated with toxicity, is required. Our hypothesis has been that protecting the gastro-intestinal tract (GIT) in HIV-1 infected individuals could alleviate the requirement for prolonged ART. We have successfully shown that the I.V infusion of a novel primatized recombinant mAb directed against integrin a4b7 just prior to and during acute SIV infection leads to a marked reduction in GIT viral loads in groups of rhesus macaques infected either intravenously or intra-rectally. More recently, using a repeated low dose intra-vaginal challenge model, we determined that administration of anti-a4b7 mAb prevented SIV transmission in 50% of challenged animals. In the remaining 50% that did become infected levels of viral DNA in GIT we found to be low or undetectable despite significant viremia. Of note, protection of GIT was associated with the reconstitution of CD4 levels in both blood and gut tissues, and a clinically healthy status for > 2 years following infection. The discordance between viral DNA in GIT and viremia suggested that virus replication in these “disease protected” animals must occur in tissues other than GIT. To identify the source of viremia we developed an in vivo localization technique that utilizes PET/CT scanning of animals administered a 64Cu-labeled anti-SIV gp120 mAb as a probe. Initial analysis of PET/CT imaging data from anti-a4b7 mAb treated and infected animals suggests that such treatment leads to marked differences in the tissues in which virus replicates, with the notable sparing of the large intestine. We conclude that protecting distinct tissues, particularly those within the GIT, may be one approach to limit the progression of disease in HIV infected patients.