title: Alpha interferon and HIV infection cause activation of human T cells in NSG-BLT mice.
abstract: The development of small animal models for the study of HIV transmission is important for evaluation of HIV prophylaxis and disease pathogenesis. In humanized bone marrow-liver-thymus (BLT) mice, hematopoiesis is reconstituted by implantation of human fetal liver and thymus tissue (Thy/Liv) plus intravenous injection of autologous liver-derived hematopoietic stem progenitor cells (HSPC). This results in reconstitution of human leukocytes in the mouse peripheral blood, lymphoid organs, and mucosal sites. NOD-scid interleukin-2 receptor-negative (IL-2Rγ(-/-)) (NSG)-BLT mice were inoculated intravaginally with HIV and were monitored for plasma viremia by a branched DNA assay 4 weeks later. T-cell activation was determined by expression of CD38 and HLA-DR on human CD4(+) and CD8(+) T cells in mouse peripheral blood at the time of inoculation and 4 weeks later. Additional BLT mice were treated with human alpha interferon 2b (IFN-α2b) (intron A) and assessed for T-cell activation. Productive HIV infection in BLT mice was associated with T-cell activation (increases in CD38 mean fluorescence intensity and both the frequency and absolute number of CD38(+) HLA-DR(+) T cells) that correlated strongly with plasma viral load and was most pronounced in the CD8(+) T-cell compartment. This T-cell activation phenotype was recapitulated in NSG-BLT mice treated with intron A. HIV susceptibility correlated with the number of HSPC injected, yet a number of mice receiving the Thy/Liv implant alone, with no HSPC injection, were also susceptible to intravaginal HIV. These results are consistent with studies linking T-cell activation to progressive disease in humans and lend support for the use of NSG-BLT mice in studies of HIV pathogenesis.
authors.affiliation: Division of Experimental Medicine, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Long
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Stoddart
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology / Q000502:physiology*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000502:physiology
chemical_list: D000077190:Interferon alpha-2; D016898:Interferon-alpha; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins