title: Progress toward a human CD4/CCR5 transgenic rat model for de novo infection by human immunodeficiency virus type 1.
abstract: The development of a permissive small animal model for the study of human immunodeficiency virus type (HIV)-1 pathogenesis and the testing of antiviral strategies has been hampered by the inability of HIV-1 to infect primary rodent cells productively. In this study, we explored transgenic rats expressing the HIV-1 receptor complex as a susceptible host. Rats transgenic for human CD4 (hCD4) and the human chemokine receptor CCR5 (hCCR5) were generated that express the transgenes in CD4(+) T lymphocytes, macrophages, and microglia. In ex vivo cultures, CD4(+) T lymphocytes, macrophages, and microglia from hCD4/hCCR5 transgenic rats were highly susceptible to infection by HIV-1 R5 viruses leading to expression of abundant levels of early HIV-1 gene products comparable to those found in human reference cultures. Primary rat macrophages and microglia, but not lymphocytes, from double-transgenic rats could be productively infected by various recombinant and primary R5 strains of HIV-1. Moreover, after systemic challenge with HIV-1, lymphatic organs from hCD4/hCCR5 transgenic rats contained episomal 2-long terminal repeat (LTR) circles, integrated provirus, and early viral gene products, demonstrating susceptibility to HIV-1 in vivo. Transgenic rats also displayed a low-level plasma viremia early in infection. Thus, transgenic rats expressing the appropriate human receptor complex are promising candidates for a small animal model of HIV-1 infection.
authors.affiliation: Gladstone Institute of Virology and Immunology, School of Medicine, University of California at San Francisco, San Francisco, CA 94141, USA.
authors.forename: Oliver T
authors.initials: OT
authors.lastname: Keppler
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Welte
authors.forename: Tuan A
authors.initials: TA
authors.lastname: Ngo
authors.forename: Peggy S
authors.initials: PS
authors.lastname: Chin
authors.forename: Kathryn S
authors.initials: KS
authors.lastname: Patton
authors.forename: Chia-Lin
authors.initials: CL
authors.lastname: Tsou
authors.forename: Nancy W
authors.initials: NW
authors.lastname: Abbey
authors.forename: Mark E
authors.initials: ME
authors.lastname: Sharkey
authors.forename: Robert M
authors.initials: RM
authors.lastname: Grant
authors.forename: Yun
authors.initials: Y
authors.lastname: You
authors.forename: John D
authors.initials: JD
authors.lastname: Scarborough
authors.forename: Wilfried
authors.initials: W
authors.lastname: Ellmeier
authors.forename: Dan R
authors.initials: DR
authors.lastname: Littman
authors.forename: Mario
authors.initials: M
authors.lastname: Stevenson
authors.forename: Israel F
authors.initials: IF
authors.lastname: Charo
authors.forename: Brian G
authors.initials: BG
authors.lastname: Herndier
authors.forename: Roberto F
authors.initials: RF
authors.lastname: Speck
authors.forename: Mark A
authors.initials: MA
authors.lastname: Goldsmith
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D015658:HIV Infections; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D008264:Macrophages / Q000276:immunology; D051381:Rats; D019713:Receptors, CCR5 / Q000235:genetics / Q000276:immunology; D014779:Virus Replication
chemical_list: D015704:CD4 Antigens; D019713:Receptors, CCR5