title: Generation of cytotoxic T cells against virus-infected human brain macrophages in a murine model of HIV-1 encephalitis.
abstract: 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 CD79alpha-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.
authors.affiliation: Center for Neurovirology and Neurodegenerative Disorders, and Department of Pathology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Larisa Y
authors.initials: LY
authors.lastname: Poluektova
authors.forename: David H
authors.initials: DH
authors.lastname: Munn
authors.forename: Yuri
authors.initials: Y
authors.lastname: Persidsky
authors.forename: Howard E
authors.initials: HE
authors.lastname: Gendelman
mesh_terms: D015526:AIDS Dementia Complex / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D000818:Animals; D001921:Brain / Q000276:immunology* / Q000473:pathology / Q000821:virology; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology / Q000821:virology; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D015683:Gene Products, gag / Q000032:analysis; D015684:Gene Products, pol / Q000032:analysis; D015497:HIV-1 / Q000235:genetics / Q000276:immunology; D006650:Histocompatibility Testing; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000235:genetics; D008212:Lymphocyte Depletion; D008264:Macrophages / Q000276:immunology* / Q000473:pathology / Q000637:transplantation / Q000821:virology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D013154:Spleen / Q000276:immunology / Q000473:pathology / Q000821:virology; D013194:Staining and Labeling; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology* / Q000821:virology
chemical_list: D015683:Gene Products, gag; D015684:Gene Products, pol; D007371:Interferon-gamma