Role of type I IFNs in the in vitro attenuation of live, temperature-sensitive vaccine strains of human respiratory syncytial virus.
The contributions of type I interferons (IFNs) to the in vitro attenuation of three temperature-sensitive (Ts) subgroup A and one subgroup B deletion mutant RSV strains were evaluated. The ability of these vaccine viruses to induce IFNs at their permissive and restrictive temperatures and their sensitivity to the antiviral effects of exogenous I IFNs were tested in human lung epithelial A549 cells. Our results show that the highly attenuated and immunogenic subgroup A vaccine strain Ts1C produced higher levels of IFN-beta than its parent RSS-2 or two related strains, Ts1A and Ts1B, at their permissive temperature. Growth of RSV-infected A549 cultures at restrictive temperatures or prior UV inactivation of the virus abolished the observed induction of IFN-beta, suggesting a strict requirement of viral replication for cellular IFN induction. The enhanced induction of IFN-beta by the highly immunogenic Ts1C at permissive temperature may be an advantageous characteristic of a live intranasal vaccine candidate. The subgroup B strain RSV B1 and its mutant cp-52 (with SH and G gene deletions) both induced similar but low levels of IFN-beta. Hence the observed overattenuation of cp-52 in human infants is probably not due to enhanced IFN induction during its replication in the host. The ability of cp-52, which does not express the SH and G proteins, to induce IFN-beta levels similar to those of its parent strain suggests that these viral proteins may not have a role in the induction of IFN-beta in the host. In addition, both subgroup A and B mutants and their respective parent strains were similarly resistant to the antiviral effects of exogenous IFN-alpha or -beta. Therefore, increased sensitivity of the mutants to IFNs does not seem to contribute to their attenuation.
Loveys
D A
DA
Laboratory of Pediatric and Respiratory Viral Diseases, DVP/CBER, Food and Drug Administration, Bethesda, MD 20892, USA.
Kulkarni
S
S
Atreya
P L
PL
D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006801:Humans; D016898:Interferon-alpha / Q000096:biosynthesis; D016899:Interferon-beta / Q000096:biosynthesis* / Q000235:genetics; D016296:Mutagenesis; D012333:RNA, Messenger; D018113:Respiratory Syncytial Virus, Human / Q000254:growth & development / Q000276:immunology*; D013696:Temperature; D014407:Tumor Cells, Cultured; D014613:Vaccines, Attenuated; D014765:Viral Vaccines / Q000276:immunology
D016898:Interferon-alpha; D012333:RNA, Messenger; D014613:Vaccines, Attenuated; D014765:Viral Vaccines; D016899:Interferon-beta