Attenuating mutations in the P/C gene of human parainfluenza virus type 1 (HPIV1) vaccine candidates abrogate the inhibition of both induction and signaling of type I interferon (IFN) by wild-type HPIV1.
Recombinant human parainfluenza virus type 1 (HPIV1) and mutants containing point and deletion (Delta) mutations in the P/C gene (r-CDelta10-15HNT553A, r-CR84G, r-CF170S and r-CDelta170), which have previously been evaluated as HPIV1 vaccine candidates, were evaluated for their effect on the type I interferon (IFN) response in vitro. HPIV1 wt infection inhibited the IFN response by inhibiting IFN regulatory factor-3 (IRF-3) activation and IFN production in A549 cells and IFN signaling in Vero cells. In contrast, r-CR84G, r-CF170S and r-CDelta170 were defective for inhibition of IRF-3 activation and IFN production and r-CF170S and r-CDelta170 did not inhibit IFN signaling. Thus, HPIV1 antagonizes the IFN response at both the level of induction and signaling, and antagonism at both levels was disrupted by mutations in the P/C gene. Because CF170S affects C and not P, the anti-IFN function can be attributed to the C proteins. These data, in the context of previous in vivo studies, suggest that the loss of antagonism of the IFN response at both the level of induction and signaling, observed with the P/C mutants, r-CF170S and r-CDelta170, was necessary for significant attenuation in African green monkeys (AGMs).
Van Cleve
William
W
Laboratory of Infectious Diseases, Respiratory Viruses Section, NIH, Bldg 50, Room 6511. 50 South Drive MSC 8007; Bethesda, MD 20892-8007, USA.
Amaro-Carambot
Emerito
E
Surman
Sonja R
SR
Bekisz
Joseph
J
Collins
Peter L
PL
Zoon
Kathryn C
KC
Murphy
Brian R
BR
Skiadopoulos
Mario H
MH
Bartlett
Emmalene J
EJ
D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D022241:Parainfluenza Vaccines / Q000235:genetics / Q000276:immunology*; D010222:Parainfluenza Virus 1, Human / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D010750:Phosphoproteins / Q000235:genetics* / Q000276:immunology; D017354:Point Mutation; D015398:Signal Transduction; D014613:Vaccines, Attenuated / Q000235:genetics / Q000276:immunology*; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics* / Q000276:immunology
D007370:Interferon Type I; D022241:Parainfluenza Vaccines; D010750:Phosphoproteins; D014613:Vaccines, Attenuated; D014764:Viral Proteins; C068855:P protein, parainfluenza virus 1; C068856:C protein, human parainfluenza virus type 1