SummaryAfter the development of highly active anti-retroviral therapy, it became clear that the majority of emergent HIV-1 is macrophage-tropic and infects CD4

Although HIV-1 can be successfully eradicated from the circulating blood of HIV-1-infected individuals using anti-retroviral therapy (ART), HIV-1 virions emerge immediately after the interruption of ART. This study was aimed to investigate the origin of the emerged HIV-1. After obtaining informed consent, blood samples from nine HIV-1-infected individuals and endoscopic ileum samples from five of the individuals were obtained. Purified peripheral mononuclear cells (PBMCs)and ileum cells were analyzed by flow-cytometry, and the V3 loop sequences of the HIV-1 envelope protein were determined. By comparing the V3 loop sequences of the samples, we confirmed that the provirus hidden in the CD4(+) PBMCs was not the source of the HIV-1 that emerged after the interruption of ART. Although free virus and HIV-1-p24 antigen (p24)-positive cells were not seen in the blood of patients receiving ART, proviral DNA and p24 could be detected in the ileum from the same patient. Among the HIV-1-infected CD4(+) cells in the ileum samples, Vα24(+) natural killer T (NKT) cells were the major p24-positive cells. These results suggest that the innate NKTcells in the mucosal compartment are the most likely candidates for the origin of the HIV-1 that emerged after ART was interrupted.