HIGH VIRAL BURDEN AND RAPID CD4(-IMMUNODEFICIENCY-VIRUS TYPE 1-INFECTED SCID-HU MICE SUGGEST DIRECT VIRAL KILLING OF THYMOCYTES IN-VIVO() CELL DEPLETION IN HUMAN)

The mechanism of CD4(+) cell loss in lymphoid organs is unknown. In th is study, human immunodeficiency virus (HIV) infection of human fetal thymus/liver implants in severe combined immunodeficient mice was used to investigate the mechanism of HIV-induced depletion of CD4-bearing cells in vivo. The implants were assessed for depletion of CD4(+) thym ocytes, apoptosis, and viral burden, We detected two phases of CD4 cel l depletion, an initial rapid phase and a more gradual later phase, Co mpared to mock-infected implants, HIV-infected implants did not demons trate detectable increases in the levels of apoptosis while severe dep letion of CD4-bearing cells was ongoing, During peak loss of CD4(+) ce lls, high viral burden was observed, suggesting that loss of CD4(+) ce lls in this in vivo system is due to direct killing of infected thymoc ytes, Increased levels of apoptosis were observed during the later pha se of thymocyte depletion; however, these apoptotic cells lacked CD4, This finding suggests that a second indirect mechanism may be responsi ble for the destruction of CD4(-) CD8(+) thymocytes in vivo. Taken tog ether, these results suggest that CD4(+) and CD4(-) cells may die by d ifferent mechanism(s).