Of virus in mice: Defining transgenic mouse models for HIV-1 research

Abstract

The pathogenesis of HIV-1 infection and the evaluation of therapeutics and vaccines can best be studied in vivo. Previously constructed mice were transgenic for expression of the cellular receptors for HIV-1, human CD4 and CCR5, under the control of the T cell-specific Lck promoter. Although splenocytes from these mice were susceptible to in vitro HIV-1 infection, the limitation of HIV-1-susceptible cells to T cells precluded the development of sustained in vivo infection. Therefore we expanded the range of susceptible cells to include monocytes/macrophages and dendritic cells by making transgenic mice with cell-specific promoters. The resulting mice were transgenic for human CD4 and CCR5 expression under the control of either the dendritic cell-specific CD11c promoter or the monocyte/macrophage-specific CD11b promoter and expressed the receptors in a cell-specific manner. In addition, the CD11c/Lck-hCD4/CCR5 mice were capable of sustaining HIV-1 infection after intrasplenic injection of virus. We bypassed the restricted entry of HIV-1 into mouse cells to focus on the post-integration phase of HIV-1 replication by constructing mice that were transgenic for a full-length infectious proviral clone of an M-tropic HIV-1 isolate (HIV-1JR-CSF) and established that the mice displayed plasma viremia. Since JR-CSF transgenic mouse cells were capable of infecting human peripheral blood mononuclear cells, we used them to develop an in vivo model to study HIV-1-infected cell reservoirs. After transfer of JR-CSF leukocytes into SCID mice that had been implanted with human thymic tissue (hu-thy/liv-SCID), we showed that treatment with highly active anti-retroviral therapy (HAART) could protect the implant from infection. After the cessation of HAART, the recipient mouse implants became HIV-1-infected by the persistent transferred JR-CSF cells. This model permits the use of defined cellular populations from the JR-CSF mice to evaluate the capacity of therapeutic interventions aimed at depleting persistent HIV-1 reservoirs. Brain microglia are the major cellular location of HIV-1 replication in the CNS and a potential reservoir of persistently infected cells. To ascertain whether JR-CSF transgenic microglia could be useful in evaluating the contribution of microglia to HIV-1-mediated disease in the CNS, we demonstrated that JR-CSF microglia produced intact virions that were infectious in vitro and in vivo.