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J. Exp. Med., Volume 187, Number 9, May 4, 1998 1439-1449

Disturbed CD4+ T Cell Homeostasis and In Vitro HIV-1 Susceptibility in Transgenic Mice Expressing T Cell Line-tropic HIV-1 Receptors

By Shinichiro Sawada,* Kavitha Gowrishankar,* Rui Kitamura,* Misao Suzuki,Dagger Gen Suzuki,§ Satoko Tahara,par and Atsushi Koitopar

From * PRESTO, Japan Science and Technology Corporation, and Tsukuba Life Science Center, The Institute of Physical and Chemical Research (RIKEN), Tsukuba, Ibaraki 305, Japan; the Dagger  Institute of Molecular Embryology and Genetics, Kumamoto University School of Medicine, Kumamoto 862, Japan; the § Division of Radiation Health, National Institute of Radiological Sciences, Inage-ku, Chiba 263, Japan; and the par  Department of Immunology, Institute of Basic Medical Sciences and Center for Tsukuba Advanced Research Alliance, Tsukuba University, Tsukuba, Ibaraki 305, Japan

T cell line-tropic (T-tropic) HIV type 1 strains enter cells by interacting 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 infection in vitro, albeit with a viral antigen production less efficient than human peripheral blood mononuclear cells. Interestingly, even without HIV infection, transgenic mice display a CD4+ T cell depletion profile of peripheral blood reminiscent of that seen in AIDS patients. We demonstrate that CD4+ T cell trafficking in transgenic mice is biased toward bone marrow essentially due to CXCR4 overexpression, resulting in the severe loss of CD4+ T cells from circulating blood. Our data suggest that CXCR4 plays an important role in lymphocyte trafficking through tissues, especially between peripheral blood and bone marrow, 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 in lymphocyte trafficking may cooperatively induce progressive HIV-1 infection and CD4+ T cell decline in patients.


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