High viral burden and rapid CD4(+) cell depletion in human immunodeficiency virus type 1-infected SCID-hu mice suggest direct viral killing of thymocytes in vivo

The mechanism of CD4(+) cell loss in lymphoid organs is unknown. In this 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(+) thymocytes, apoptosis, and viral burden, We detected two phases of CD4 cell depletion, an initial rapid phase and a more gradual later phase, Compared to mock-infected implants, HIV-infected implants did not demonstrate detectable increases in the levels of apoptosis while severe depletion of CD4-bearing cells was ongoing, During peak loss of CD4(+) cells, high viral burden was observed, suggesting that loss of CD4(+) cells in this in vivo system is due to direct killing of infected thymocytes, Increased levels of apoptosis were observed during the later phase of thymocyte depletion; however, these apoptotic cells lacked CD4, This finding suggests that a second indirect mechanism may be responsible for the destruction of CD4(-) CD8(+) thymocytes in vivo. Taken together, these results suggest that CD4(+) and CD4(-) cells may die by different mechanism(s).