title: Disseminated and sustained HIV infection in CD34+ cord blood cell-transplanted Rag2-/-gamma c-/- mice.
abstract: Because of species selectivity, HIV research is largely restricted to in vitro or clinical studies, both limited in their ability to rapidly assess new strategies to fight the virus. To prospectively study some aspects of HIV in vivo, immunodeficient mice, transplanted with either human peripheral blood leukocytes or human fetal tissues, have been developed. Although these are susceptible to HIV infection, xenoreactivity, and short infection spans, resource and ethical constraints, as well as biased HIV coreceptor tropic strain infection, pose substantial problems in their use. Rag2(-/-)gamma(c)(-/-) mice, transplanted as newborns with human CD34(+) cells, were recently shown to develop human B, T, and dendritic cells, constituting lymphoid organs in situ. Here we tested these mice as a model system for HIV-1 infection. HIV RNA levels peaked to up to 2 x 10(6) copies per milliliter of plasma early after infection, and viremia was observed for up to 190 days, the longest time followed. A marked relative CD4(+) T cell depletion in peripheral blood occurred in CXCR4-tropic strain-infected mice, whereas this was less pronounced in CCR5-tropic strain-infected animals. Thymus infection was almost exclusively observed in CXCR4-tropic strain-infected mice, whereas spleen and lymph node HIV infection occurred irrespective of coreceptor selectivity, consistent with respective coreceptor expression on human CD4(+) T cells. Thus, this straightforward to generate and cost-effective in vivo model closely resembles HIV infection in man and therefore should be valuable to study virus-induced pathology and to rapidly evaluate new approaches aiming to prevent or treat HIV infection.
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Baenziger
authors.forename: Roxane
authors.initials: R
authors.lastname: Tussiwand
authors.forename: Erika
authors.initials: E
authors.lastname: Schlaepfer
authors.forename: Luca
authors.initials: L
authors.lastname: Mazzucchelli
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
authors.forename: Michael O
authors.initials: MO
authors.lastname: Kurrer
authors.forename: Silvia
authors.initials: S
authors.lastname: Behnke
authors.forename: Joachim
authors.initials: J
authors.lastname: Frey
authors.forename: Annette
authors.initials: A
authors.lastname: Oxenius
authors.forename: Helen
authors.initials: H
authors.lastname: Joller
authors.forename: Adriano
authors.initials: A
authors.lastname: Aguzzi
authors.forename: Markus G
authors.initials: MG
authors.lastname: Manz
authors.forename: Roberto F
authors.initials: RF
authors.lastname: Speck
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis*; D001402:B-Lymphocytes / Q000276:immunology / Q000821:virology; D036101:Cord Blood Stem Cell Transplantation; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism / Q000601:surgery / Q000821:virology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008221:Lymphoid Tissue / Q000276:immunology / Q000378:metabolism / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D019713:Receptors, CCR5 / Q000276:immunology / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
chemical_list: D018952:Antigens, CD34; D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D016692:Receptors, Antigen, T-Cell, gamma-delta; D019713:Receptors, CCR5; D019718:Receptors, CXCR4