title: Recombinant human parainfluenza virus type 2 with mutations in V that permit cellular interferon signaling are not attenuated in non-human primates.
abstract: The HPIV2 V protein inhibits type I interferon (IFN) induction and signaling. To manipulate the V protein, whose coding sequence overlaps that of the polymerase-associated phosphoprotein (P), without altering the P protein, we generated an HPIV2 virus in which P and V are expressed from separate genes (rHPIV2-P+V). rHPIV2-P+V replicated like HPIV2-WT in vitro and in non-human primates. HPIV2-P+V was modified by introducing two separate mutations into the V protein to create rHPIV2-L101E/L102E and rHPIV2-Delta122-127. In contrast to HPIV2-WT, both mutant viruses were unable to degrade STAT2, leaving virus-infected cells susceptible to IFN. Neither mutant, nor HPIV2-WT, induced significant amounts of IFN-beta in infected cells. Surprisingly, neither rHPIV2-L101E/L102E nor rHPIV2-Delta122-127 was attenuated in two species of non-human primates. This indicates that loss of HPIV2's ability to inhibit IFN signaling is insufficient to attenuate virus replication in vivo as long as IFN induction is still inhibited.
authors.affiliation: Laboratory of Infectious Diseases, RNA Viruses Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA. schaapa@niaid.nih.gov
authors.forename: Anne
authors.initials: A
authors.lastname: Schaap-Nutt
authors.forename: Christopher
authors.initials: C
authors.lastname: D'Angelo
authors.forename: Emerito
authors.initials: E
authors.lastname: Amaro-Carambot
authors.forename: Sheila M
authors.initials: SM
authors.lastname: Nolan
authors.forename: Stephanie
authors.initials: S
authors.lastname: Davis
authors.forename: Shenelle-Marie
authors.initials: SM
authors.lastname: Wise
authors.forename: Caraline
authors.initials: C
authors.lastname: Higgins
authors.forename: Konrad
authors.initials: K
authors.lastname: Bradley
authors.forename: Olivia
authors.initials: O
authors.lastname: Kim
authors.forename: Reina
authors.initials: R
authors.lastname: Mayor
authors.forename: Mario H
authors.initials: MH
authors.lastname: Skiadopoulos
authors.forename: Peter L
authors.initials: PL
authors.lastname: Collins
authors.forename: Brian R
authors.initials: BR
authors.lastname: Murphy
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002522:Chlorocebus aethiops; D004279:DNA, Viral / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D005814:Genes, Viral; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology; D007372:Interferons / Q000502:physiology*; D008253:Macaca mulatta; D009154:Mutation; D016366:Open Reading Frames; D010223:Parainfluenza Virus 2, Human / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics; D011323:Primates / Q000276:immunology / Q000821:virology*; D011994:Recombinant Proteins; D015398:Signal Transduction; D013045:Species Specificity; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics* / Q000276:immunology; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics / Q000276:immunology
chemical_list: C091435:DDB1 protein, human; D004279:DNA, Viral; D004268:DNA-Binding Proteins; D007370:Interferon Type I; C407030:P protein, Human parainfluenza virus 2; D010750:Phosphoproteins; D011994:Recombinant Proteins; C068854:V protein, human parainfluenza virus type 1; D014764:Viral Proteins; D007372:Interferons