title: Accessory genes confer a high replication rate to virulent feline immunodeficiency virus.
abstract: Feline immunodeficiency virus (FIV) is a lentivirus that causes AIDS in domestic cats, similar to human immunodeficiency virus (HIV)/AIDS in humans. The FIV accessory protein Vif abrogates the inhibition of infection by cat APOBEC3 restriction factors. FIV also encodes a multifunctional OrfA accessory protein that has characteristics similar to HIV Tat, Vpu, Vpr, and Nef. To examine the role of vif and orfA accessory genes in FIV replication and pathogenicity, we generated chimeras between two FIV molecular clones with divergent disease potentials: a highly pathogenic isolate that replicates rapidly in vitro and is associated with significant immunopathology in vivo, FIV-C36 (referred to here as high-virulence FIV [HV-FIV]), and a less-pathogenic strain, FIV-PPR (referred to here as low-virulence FIV [LV-FIV]). Using PCR-driven overlap extension, we produced viruses in which vif, orfA, or both genes from virulent HV-FIV replaced equivalent genes in LV-FIV. The generation of these chimeras is more straightforward in FIV than in primate lentiviruses, since FIV accessory gene open reading frames have very little overlap with other genes. All three chimeric viruses exhibited increased replication kinetics in vitro compared to the replication kinetics of LV-FIV. Chimeras containing HV-Vif or Vif/OrfA had replication rates equivalent to those of the virulent HV-FIV parental virus. Furthermore, small interfering RNA knockdown of feline APOBEC3 genes resulted in equalization of replication rates between LV-FIV and LV-FIV encoding HV-FIV Vif. These findings demonstrate that Vif-APOBEC interactions play a key role in controlling the replication and pathogenicity of this immunodeficiency-inducing virus in its native host species and that accessory genes act as mediators of lentiviral strain-specific virulence.
authors: Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA.
authors: Ryan M
authors: RM
authors: Troyer
authors: Jesse
authors: J
authors: Thompson
authors: John H
authors: JH
authors: Elder
authors: Sue
authors: S
authors: VandeWoude
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002415:Cats / Q000821:virology*; D002460:Cell Line; D002678:Chimera / Q000821:virology; D043525:Cytosine Deaminase / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D016346:Gene Products, vif / Q000378:metabolism* / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D016089:Immunodeficiency Virus, Feline / Q000472:pathogenicity* / Q000502:physiology; D016133:Polymerase Chain Reaction; D034622:RNA Interference; D053262:Receptors, OX40 / Q000378:metabolism; D013045:Species Specificity; D054334:Viral Regulatory and Accessory Proteins / Q000378:metabolism* / Q000502:physiology; D014774:Virulence; D014779:Virus Replication / Q000502:physiology*
chemical_list: D017931:DNA Primers; D016346:Gene Products, vif; D053262:Receptors, OX40; D054334:Viral Regulatory and Accessory Proteins; D043525:Cytosine Deaminase
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