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The Journal of Immunology, 2002, 168: 3941-3949.
Copyright © 2002 by The American Association of Immunologists

Generation of Cytotoxic T Cells Against Virus-Infected Human Brain Macrophages in a Murine Model of HIV-1 Encephalitis1

Larisa Y. Poluektova2,*, David H. Munn{ddagger}, Yuri Persidsky3,* and Howard E. Gendelman3,*,{dagger}

* Center for Neurovirology and Neurodegenerative Disorders, and Departments of Pathology and Microbiology and {dagger} Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198; and {ddagger} Program in Molecular Immunology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA 30912

HIV-1 encephalitis (HIVE) and its associated dementia can occur in up to 20% of infected individuals, usually when productive viral replication in brain mononuclear phagocytes (macrophages and microglia) and depletion of CD4+ T lymphocytes are most significant. T cells control viral replication through much of HIV-1 disease, but how this occurs remains incompletely understood. With this in mind, we studied HIV-1-specific CTL responses in a nonobese diabetic (NOD)-SCID mouse model of HIVE. HIV-1-infected monocyte-derived macrophages (MDM) were injected into the basal ganglia after syngeneic immune reconstitution by HLA-A*0201-positive human PBL to generate a human PBL-NOD-SCID HIVE mouse. Engrafted T lymphocytes produced HIV-1gag- and HIV-1pol-specific CTL against virus-infected brain MDM within 7 days. This was demonstrated by tetramer staining of human PBL in mouse spleens and by IFN-{gamma} ELISPOT. CD8, granzyme B, HLA-DR, and CD45R0 Ag-reactive T cells and CD79{alpha}-positive B cells migrated to and were in contact with human MDM in brain areas where infected macrophages were abundant. The numbers of productively infected MDM were markedly reduced (>85%) during 2 wk of observation. The human PBL-NOD-SCID HIVE mouse provides a new tool for studies of cellular immune responses against HIV-1-infected brain mononuclear phagocytes during natural disease and after vaccination.




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