Determinants of the Host Range Restriction of Replication of Bovine Parainfluenza Virus Type 3 in Rhesus Monkeys Are Polygenic

Abstract

The Kansas strain of bovine parainfluenza virus type 3 (BPIV3) is 100-to 1,000-fold restricted in replication in the respiratory tracts of nonhuman primates compared to human PIV3 (HPIV3), an important pathogen of infants and young children. BPIV3 is also restricted in replication in human infants and children, yet it is immunogenic and is currently being evaluated in clinical trials as a vaccine candidate to protect against illness caused by HPIV3. We have examined the genetic basis for the host range attenuation phenotype of BPIV3 by exchanging each open reading frame (ORF) of a recombinant wild-type HPIV3 with the analogous ORF from BPIV3, with the caveats that the multiple ORFs of the P gene were exchanged as a single unit and that the HN and F genes were exchanged as a single unit. Recombinant chimeric bovine-human PIV3s were recovered from cDNA, and the levels of viral replication in vitro and in the respiratory tract of rhesus monkeys were determined. Recombinant chimeric HPIV3s bearing the BPIV3 N or P ORF were highly attenuated in the upper and lower respiratory tracts of monkeys, whereas those bearing the BPIV3 M or L ORF or the F and HN genes were only moderately attenuated. This indicates that the genetic determinants of the host range restriction of replication of BPIV3 for primates are polygenic, with the major determinants being the N and P ORFs. Monkeys immunized with these bovine-human chimeric viruses, including the more highly attenuated ones, developed higher levels of HPIV3 hemagglutination-inhibiting serum antibodies than did monkeys immunized with BPIV3 and were protected from challenge with wild-type HPIV3. Furthermore, host range determinants could be combined with attenuating point mutations to achieve an increased level of attenuation. Thus, chimeric recombinant bovine-human PIV3 viruses that manifest different levels of attenuation in rhesus monkeys are available for evaluation as vaccine candidates to protect infants from the severe lower respiratory tract disease caused by HPIV3.Human parainfluenza virus type 3 (HPIV3) and its animal counterpart, bovine PIV3 (BPIV3), are enveloped, nonsegmented negative-strand RNA viruses of the genus Respirovirus in the family Paramyxoviridae (4, 26). HPIV3 is a common cause of respiratory disease in infants (8, 28), and presently a licensed vaccine is not available. HPIV3 and BPIV3 share a moderate to high level of nucleotide and amino acid sequence identity (2) and are 25% antigenically related by cross-neutralization studies (6). The Kansas strain of BPIV3 is restricted in replication in the respiratory tracts of humans and nonhuman primates (6, 23) and is being evaluated as a candidate vaccine to prevent the severe lower respiratory tract disease caused by infection of infants and young children with 27).BPIV3 and HPIV3 have the same genome organization (4), encoding nine proteins from six contiguous genes. These nine proteins include the three nucleocapsid-associated proteins, the nucleoprotein (N), the phosphoprotein (P) and the large polymer...

Newcastle disease virus, a host range-restricted virus, as a vaccine vector for intranasal immunization against emerging pathogens

“…It also might be that NDV is less able to block the type I IFN response in primate cells, as suggested by previous studies (40). In the case of the host range restriction of bovine parainfluenza virus type 3 in primates, each gene appeared to make a contribution (41). Regardless of the mechanism, it is clear that NDV is very highly restricted for replication in primates, and the level of restriction appears to be similar for the mesogenic and lentogenic pathotypes based on this work and that performed previously (31).…”

New Generation Live Vaccines against Human Respiratory Syncytial Virus Designed by Reverse Genetics

“…A similar strategy has been successful for HPIV3, which has a bovine counterpart, bovine parainfluenza virus (BPIV) type 3 that is attenuated in primates. Combining the HPIV3 antigenic determinants with backbones containing one or more BPIV3 genes has generated several attenuated derivatives suitable for clinical evaluation (31,32).…”

Parainfluenza Virus Type 3 Expressing the Native or Soluble Fusion (F) Protein of Respiratory Syncytial Virus (RSV) Confers Protection from RSV Infection in African Green Monkeys

“…The capacity of the bPIV3 vaccine to replicate in the nasal cavity without causing respiratory illness demonstrated its attenuation in young seronegative children (20). With a rhesus monkey attenuation model, it was shown that b/h PIV3 retained the attenuation phenotype despite the presence of the hPIV3 F and HN genes (33,35).…”