DISTURBED CD4(-CELL HOMEOSTASIS AND IN-VITRO HIV-1 SUSCEPTIBILITY IN TRANSGENIC MICE EXPRESSING T-CELL LINE-TROPIC HIV-1 RECEPTORS() T)

T cell line-tropic (T-tropic) HIV type 1 strains enter cells by intera cting with the cell-surface molecules CD4 and CXCR4. We have generated transgenic mice predominantly expressing human CD4 and CXCR4 on their CD4-positive T lymphocytes (CD4(+) T cells). Their primary thymocytes are susceptible to T-tropic but not to macrophage-tropic HIV-1 infect ion in vitro, albeit with a viral antigen production less efficient th an human peripheral blood mononuclear cells. Interestingly, even witho ut HIV infection, transgenic mice display a CD4(+) T cell depletion pr ofile of peripheral blood reminiscent of that seen in AIDS patients. W e demonstrate that CD4(+) T cell trafficking in transgenic mice is bia sed toward bone marrow essentially due to CXCR4 overexpression, result ing in the severe loss of CD4(+) T cells from circulating blood. Our d ata suggest that CXCR4 plays an important role in lymphocyte trafficki ng through tissues, especially between peripheral blood and bone marro w, participating in the regulation of lymphocyte homeostasis in these compartments. Based on these findings, we propose a hypothetical model in which the dual function of CXCR4 in HIV-1 infection and ill lympho cyte trafficking may cooperatively induce progressive HIV-1 infection and CD4(+) T cell decline in patients.