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Shinichiro Sawada^*, Kavitha Gowrishankar^*, Rui Kitamura^*, Misao Suzuki, Gen Suzuki, Satoko Tahara^||, and Atsushi Koito^||

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 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 ^|| 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.

Abbreviations used: CD4 (and CD8) SP, CD4 (and CD8) single positive; h, human; m, murine; M-tropic, macrophage-tropic; MIP, macrophage inflammatory protein; RANTES, regulated on activation, normal T cell expressed and secreted; SDF-1, stromal cell–derived factor 1; T-tropic, T cell line–tropic.

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