Here we show that transplantation of autologous human hematopoietic fetal liver CD34+ cells into NOD/SCID mice previously implanted with human fetal thymic and liver tissues results in long-term, systemic human T-cell homeostasis. In addition, these mice show systemic repopulation with human B cells, monocytes and macrophages, and dendritic cells (DCs). T cells in these mice generate human major histocompatibility complex class I- and class II-restricted adaptive immune responses to Epstein-Barr virus (EBV) infection and are activated by human DCs to mount a potent T-cell immune response to superantigens. Administration of the superantigen toxic shock syndrome toxin 1 (TSST-1) results in the specific systemic expansion of human Vbeta2+ T cells, release of human proinflammatory cytokines and localized, specific activation and maturation of human CD11c+ dendritic cells. This represents the first demonstration of long-term systemic human T-cell reconstitution in vivo allowing for the manifestation of the differential response by human DCs to TSST-1.

Intrarectal infection between men who have sex with men represents a predominant form of human immunodeficiency virus (HIV) transmission in developed countries. Currently there are no adequate small animal models that recapitulate intrarectal HIV transmission. Here we demonstrate that human lymphocytes generated in situ from hematopoietic stem cells reconstitute the gastrointestinal tract of humanized mice with human CD4+ T cells rendering them susceptible to intrarectal HIV transmission. HIV infection after a single intrarectal inoculation results in systemic infection with depletion of CD4+ T cells in gut-associated lymphoid tissue and other pathologic sequela that closely mimics those observed in HIV infected humans. This novel model provides the basis for the development and evaluation of novel approaches aimed at immune reconstitution of human gut-associated lymphoid tissue and for the development, testing, and implementation of microbicides to prevent intrarectal HIV-1 transmission.

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