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The gastrointestinal tract is the site of early abundant HIV replication and associated marked CD4 + T-cell depletion. The aim of this study was to characterize the basis for the increased HIV replication in this compartment. Isolated mononuclear cells of the peripheral blood (PBMCs), the intestinal lamina propria (LPMCs), and purified gut lamina propria CD4 + T-cell subpopulations (LP T cells) were isolated, phenotypically characterized, and infected in vitro with 2 different HIV-1 strains. T-cell subpopulations were analyzed by fluorescence-activated cell sorter. HIV- 1 core protein p24 was determined in supernatants after in vitro infection. Furthermore the effect of T-cell stimulation on the replication of M- and T-tropic HIV strains was studied. In vitro replication of HIV-1 was significantly increased in CD69 high compared with CD69 low CD4 + LP T cells, while there was no difference between CD103 - and CD103 + CD4 + LP T cells. Experimental stimulation of LPMCs, which mimics activation by intestinal pathogens frequently present in the bowel of HIV-infected patients, further dramatically enhances HIV replication (24.5-fold) compared with nonstimulated LPMCs. M-tropic HIV-1 showed a preferential replication in LPMCs, while T-tropic HIV-1 strain showed a preferential replication in PBMCs. Thus, the elevated activation state of target cells in the intestine and not the expression of the homing marker CD103 is directly linked to massive HIV production.