title: Susceptibility of rat-derived cells to replication by human immunodeficiency virus type 1.
abstract: Progress in developing a small animal model of human immunodeficiency virus type 1 (HIV-1) disease would greatly facilitate studies of transmission, pathogenesis, host immune responses, and antiviral strategies. In this study, we have explored the potential of rats as a susceptible host. In a single replication cycle, rat cell lines Rat2 and Nb2 produced infectious virus at levels 10- to 60-fold lower than those produced by human cells. Rat-derived cells supported substantial levels of early HIV-1 gene expression, which was further enhanced by overexpression of human cyclin T1. Rat cells displayed quantitative, qualitative, and cell-type-specific limitations in the late phase of the HIV-1 replication cycle including relative expression levels of HIV-1 Gag proteins, intracellular Gag processing, and viral egress. Nb2 cells were rendered permissive to HIV-1 R5 viruses by coexpression of human CD4 and CCR5, indicating that the major restriction on HIV-1 replication was at the level of cellular entry. We also found that primary rat lymphocytes, macrophages, and microglia expressed considerable levels of early HIV-1 gene products following infection with pseudotyped HIV-1. Importantly, primary rat macrophages and microglia, but not lymphocytes, also expressed substantial levels of HIV-1 p24 CA and produced infectious virions. Collectively, these results identify the rat as a promising candidate for a transgenic small animal model of HIV-1 infection and highlight pertinent cell-type-specific restrictions that are features of this species.
authors.affiliation: Gladstone Institute of Virology and Immunology, School of Medicine, University of California San Francisco, San Francisco, California 94141-9100, USA.
authors.forename: O T
authors.initials: OT
authors.lastname: Keppler
authors.forename: W
authors.initials: W
authors.lastname: Yonemoto
authors.forename: F J
authors.initials: FJ
authors.lastname: Welte
authors.forename: K S
authors.initials: KS
authors.lastname: Patton
authors.forename: D
authors.initials: D
authors.lastname: Iacovides
authors.forename: R E
authors.initials: RE
authors.lastname: Atchison
authors.forename: T
authors.initials: T
authors.lastname: Ngo
authors.forename: D L
authors.initials: DL
authors.lastname: Hirschberg
authors.forename: R F
authors.initials: RF
authors.lastname: Speck
authors.forename: M A
authors.initials: MA
authors.lastname: Goldsmith
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D056906:Cyclin T; D016213:Cyclins / Q000378:metabolism; D004195:Disease Models, Animal; D015658:HIV Infections / Q000821:virology*; D016325:HIV Long Terminal Repeat / Q000502:physiology; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000821:virology*; D008562:Membrane Glycoproteins; D051379:Mice; D017628:Microglia / Q000821:virology*; D051381:Rats; D019713:Receptors, CCR5 / Q000378:metabolism; D013601:T-Lymphocytes / Q000821:virology*; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication
chemical_list: C503684:CCNT1 protein, human; D015704:CD4 Antigens; C503685:Ccnt1 protein, mouse; C503686:Ccnt1 protein, rat; D056906:Cyclin T; D016213:Cyclins; C028391:G protein, vesicular stomatitis virus; D008562:Membrane Glycoproteins; D019713:Receptors, CCR5; D014759:Viral Envelope Proteins; D014764:Viral Proteins