Human CD4+ T cells (brown) repopulate mucosal tissues in humanized mice.

Sexually transmitted HIV begins its battle with the immune system in the mucosal tissues of the host gut. Sun et al. (page 705) now recapitulate these events for the first time in a small animal model by replacing a mouse immune system with human lymphocytes.

Mice that lack their own T and B lymphocytes can be humanized by grafting them with human bone marrow, fetal liver, and fetal thymic tissue (BLT). This environment supports the development of human stem cells into various immune cell lineages, but it was not yet clear whether the cells were fully functional and homed to the appropriate tissues.

Sun and colleagues now use this system to show that human lymphocytes, including CD4+ T cells expressing the HIV coreceptors CCR5 and CXCR4, are able to migrate into the lymphoid tissues in the mouse gut and repopulate these areas. The mice were highly susceptible to intrarectal HIV infection, a common route of transmission. The mice displayed the same disease pathology as that seen in humans—systemic viral infection and CD4+ T cell depletion from their tissues—and even produced human antibodies against the virus.

This model offers a significant advantage over current primate models, which only permit infection with SIV or SIV/HIV chimeric viruses. “We finally have a way to follow HIV in a system that is as close to the human situation as you can get,” says senior author J. Victor Garcia. The researchers plan to test their model for susceptibility to intravaginal HIV infection and to understand how the virus traverses mucosal barriers. The mice should also be useful in preclinical screens for microbicides, vaccines, and preventive drugs.