Bovine Parainfluenza Virus Type 3 (BPIV3) Fusion and Hemagglutinin-Neuraminidase Glycoproteins Make an Important Contribution to the Restricted Replication of BPIV3 in Primates

Laboratory of Infectious Disease, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Journal of Virology (Impact Factor: 4.44). 11/2000; 74(19):8922-9. DOI: 10.1128/JVI.74.19.8922-8929.2000
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This study examines the contribution of the fusion (F) and hemagglutinin-neuraminidase (HN) glycoprotein genes of bovine parainfluenza virus type 3 (BPIV3) to its restricted replication in the respiratory tract of nonhuman primates. A chimeric recombinant human parainfluenza type 3 virus (HPIV3) containing BPIV3 F and HN glycoprotein genes in place of its own and the reciprocal recombinant consisting of BPIV3 bearing the HPIV3 F and HN genes (rBPIV3-F(H)HN(H)) were generated to assess the effect of glycoprotein substitution on replication of HPIV3 and BPIV3 in the upper and lower respiratory tract of rhesus monkeys. The chimeric viruses were readily recovered and replicated in simian LLC-MK2 cells to a level comparable to that of their parental viruses, suggesting that the heterologous glycoproteins were compatible with the PIV3 internal proteins. HPIV3 bearing the BPIV3 F and HN genes was restricted in replication in rhesus monkeys to a level similar to that of its BPIV3 parent virus, indicating that the glycoprotein genes of BPIV3 are major determinants of its host range restriction of replication in rhesus monkeys. rBPIV3-F(H)HN(H) replicated in rhesus monkeys to a level intermediate between that of HPIV3 and BPIV3. This observation indicates that the F and HN genes make a significant contribution to the overall attenuation of BPIV3 for rhesus monkeys. Furthermore, it shows that BPIV3 sequences outside the F and HN region also contribute to the attenuation phenotype in primates, a finding consistent with the previous demonstration that the nucleoprotein coding sequence of BPIV3 is a determinant of its attenuation for primates. Despite its restricted replication in the respiratory tract of rhesus monkeys, rBPIV3-F(H)HN(H) conferred a level of protection against challenge with HPIV3 that was indistinguishable from that induced by previous infection with wild-type HPIV3. The usefulness of rBPIV3-F(H)HN(H) as a vaccine candidate against HPIV3 and as a vector for other viral antigens is discussed.

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Available from: Mario Skiadopoulos, Mar 28, 2014
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    • "These strains elicited an improved antibody response and, in monkeys , protected against HPIV-3 infection. Two of the chimeric viruses, one containing the HN gene from the bovine virus in a human virus background and the other containing the F and HN glycoprotein genes from the human virus in the bovine virus background are now viewed as the strongest vaccine candidates for human trials [96] [97] [98]. The latter candidate combines the host range restriction of BPIV-3 with the major antigenic determinants of HPIV-3, permitting efficient replication in vitro (which is beneficial for vaccine development) along with host range phenotype and excellent antigenicity . "
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    Pediatric Clinics of North America 11/2006; 53(5):929-59, ix-x. DOI:10.1016/j.pcl.2006.08.004 · 2.12 Impact Factor
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    • "The attenuation phenotype of BPIV3 has been characterized in detail, and its polygenic nature, based on a great number of host range mutations, should guarantee stability following replication in vivo and should provide for added safety in a live-attenuated vaccine (Skiadopoulos et al., 2003). A recombinant version of BPIV3 was generated, and antigenic chimeric viruses in which the HN and F antigens of BPIV3 are replaced by those of HPIV3 (rB/HPIV3) are now available as vectors (Schmidt et al., 2000). rB/HPIV3 viruses replicate to high titer (10 8.0 TCID 50 /ml) in vitro and should be infectious in humans at 10 5.0 TCID 50 , thus economical to produce. "
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    • "It is expected that the bPIV3/RSV(I) virus will display all of the desirable restricted replication characteristics in humans, since all of the attenuation determinants were retained in the bPIV3 vaccine genome. This is the advantage bPIV3 has over the related virus vector, a chimeric bovine/human PIV3, which may have lost potential attenuation-determining sequences by substituting the bPIV3 F and HN genes with those of hPIV3 (Schmidt et al., 2000). The safety of RSV vaccines is an important concern, since the vaccine will be administered to infants. "
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    ABSTRACT: Parainfluenza virus type 3 (PIV3) and respiratory syncytial virus (RSV) are the main causes of ubiquitous acute respiratory diseases of infancy and early childhood, causing 20-25 % of pneumonia and 45-50 % of bronchiolitis in hospitalized children. The primary goal of this study was to create an effective and safe RSV vaccine based on utilizing attenuated bovine PIV3 (bPIV3) as a virus vector backbone. bPIV3 had been evaluated in human clinical trials and was shown to be attenuated and immunogenic in children as young as 2 months of age. The ability of bPIV3 to function as a virus vaccine vector was explored further by introducing the RSV attachment (G) and fusion (F) genes into the bPIV3 RNA genome. The resulting virus, bPIV3/RSV(I), contained an insert of 2900 nt, comprising two translationally competent transcription units. Despite this increase in genetic material, the virus replicated to high titres in Vero cells. This recombinant virus expressed the RSV G and F proteins sufficiently to evoke a protective immune response in hamsters upon challenge with RSV or human PIV3 and to elicit RSV neutralizing and PIV3 haemagglutinin inhibition serum antibodies. In effect, a bivalent vaccine was produced that could protect vaccinees from RSV as well as PIV3. Such a vaccine would vastly reduce the respiratory disease burden, the associated hospitalization costs and, most importantly, decrease morbidity and mortality of infants, immunocompromised individuals and the elderly.
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