Despite extensive correlative studies of HIV-infected persons and ex vivo studies of their peripheral blood immune cells, fundamental questions about HIV pathogenesis and immunity remain unanswered. Secondary and mucosa-associated lymphoid tissues are particularly important in HIV infection as primary sites of viral replication and CD4+ T cell depletion, and immune responses, but difficult to study in humans. To study host-pathogen interactions in tissue compartments, and effects of perturbations of immune responses, investigators have turned to animal models. Unfortunately, an ideal animal model of HIV infection has remained elusive. Although simian immunodeficiency virus (SIV) infection of rhesus macaques has provided many critically important insights into retroviral pathogenesis and immunity, there are differences inherent in macaque immune responses to SIV and human responses to HIV. The utility of the traditional mouse model for HIV infection has been limited by HIV's inability to productively infect mouse immune cells. To circumvent this, chimeric "humanized mice" with human immune cells and/or tissues have been generated. Building on earlier models, HU CFAR Core H has been able to make an improved humanized BLT (bone marrow-liver-thymus) mouse model widely available that allows CFAR members to model the development of humoral and cellular human immune responses to HIV, and mucosal transmission of HIV. Working with multiple HU CFAR investigators during the past funding period. Core H has demonstrated that BLT mice recapitulate an "eclipse phase" of HIV infection immediately following exposure of the vaginal mucosa to HIV challenge;generate functional human cellular and humoral immune responses to HIV;and support advanced in vivo imaging of HIV infection by multiphoton-intravital microscopy and bioluminescence imaging. In the coming funding period. Core H will provide access to BLT and other models of humanized mice as a newly named Humanized Mouse Core. Core H will generate these mice and perform experimental procedures including HIV infection with them for all requesting HU CFAR investigators. Additionally, Core H will continue to work on improving the humanized mouse models of HIV that they provide, to expand the areas of investigation that these models can support.
Specific aims of this Core include: 1. Generation of humanized BLT mice. 2. Generation of Hu-HSC mice and Hu-PBL mice. 3. Performance of experimental procedures on humanized mice. 4. Further improvement of humanized mouse models of HIV.

Public Health Relevance

Despite effective treatments, HIV/AIDS remains a leading cause of death and lost years of productive life worldwide. New interventions to prevent or treat HIV are therefore urgently needed, but their development will require better understanding of HIV transmission and pathogenesis, and anti-HIV immune responses. By providing an improved humanized mouse model of HIV infection. Core H will enable HU CFAR members to investigate HIV pathogenesis and transmission, and human anti-HIV immune responses, in vivo.

National Institute of Health (NIH)
Center Core Grants (P30)
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Special Emphasis Panel (ZAI1)
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Harvard Medical School
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