Recombinant human parainfluenza virus type 2 with mutations in V that permit cellular interferon signaling are not attenuated in non-human primates.
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.
Schaap-Nutt
Anne
A
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
D'Angelo
Christopher
C
Amaro-Carambot
Emerito
E
Nolan
Sheila M
SM
Davis
Stephanie
S
Wise
Shenelle-Marie
SM
Higgins
Caraline
C
Bradley
Konrad
K
Kim
Olivia
O
Mayor
Reina
R
Skiadopoulos
Mario H
MH
Collins
Peter L
PL
Murphy
Brian R
BR
Schmidt
Alexander C
AC
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
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