The Goldstein laboratory investigates various aspects of HIV infection using novel murine models they developed that are chimeric for the human immune system. Human thymus and liver implanted in mice with an intrinsic defect in their B cells and T cells (thy/liv-SCID-hu mice) grow significantly and repopulate the periphery of these mice with human T cells. The periphery of our thy/liv-SCID-hu mice has significant numbers of human T cells and this permits the development of disseminated HIV infection in these mice after either intra-implant injection or intra-peritoneal inoculation of HIV. In addition, novel transgenic mice have been developed expressing human CD4 and CCR5 or the full length HIV genome that develop HIV infection. These mice are being used to explore the immunopathogenesis of HIV infection including the investigation of the mechanism of HIV dissemination, the effect of HIV on thymic maturation, the effect of cytokines on HIV replication, the emergence of phenotypic variants during in vivo infection and the efficacy of various therapeutic interventions targeted to HIV.

Approximately 20% of HIV-1-infected infected individuals develop neurological disease associated with the presence of HIV-1-infected cells in the brain. The effectiveness of highly active antiretroviral therapy (HAART) in markedly reducing plasma viral loads has raised the possibility that HIV infection may be successfully "purged" from the systemic immune system. However, HIV-1-infected cells in the brain may function as an important reservoir from which HIV can be reintroduced back into the lymphoid tissues after cessation of anti-retroviral therapy. Therefore, they are determining if the brain can function as an in vivo sanctuary for HIV-1-infected cells such as microglia that can migrate from the brain and infect peripheral lymphoid tissues. In addition, they are examining the in vivo effectiveness of a novel therapeutic approach consisting of HAART combined with targeted toxin therapy to reduce the numbers of HIV-1-infected cells in the brain. They are also studying the mechanisms of in vivo trafficking of HIV-1-infected cells into the brain. Although much is known about the clinical manifestations of HIV dementia, there are many gaps in our understanding of the pathophysiology of the disease including the mechanism by which HIV crosses the blood brain barrier. There is much data to support the possibility that HIV-1 infection is introduced into the brain by the infiltration of HIV-1-infected cells. The Goldstein laboratory is examining the mechanism of entry of HIV-1-infected cells by investigating the in vivo effect of different factors such as cellular activation, chemokine production and cytokine secretion on the migration of HIV-1-infected cells into the brain. Information generated from these studies should provide insights into the mechanism of cellular trafficking into the brain that may permit the development and in vivo testing of new therapeutic strategies aimed at preventing entry of HIV-1-infected cells into the brain. Blocking the migration of HIV-1-infected cells into the brain may be an important new therapeutic strategy to use for acutely infected individuals and for infants born to HIV-1-infected mothers. These in vivo studies are being be performed using novel transgenic mouse models that they have recently developed that display productive HIV-1 infection.