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: 4.65). 11/2000; 74(19):8922-9. DOI: 10.1128/JVI.74.19.8922-8929.2000
Source: PubMed

ABSTRACT 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Human parainfluenza virus type 3 (HPIV3) is a common cause of upper and lower respiratory tract illness in infants and young children. Live-attenuated cold-adapted HPIV3 vaccines have been evaluated in infants but a suitable interval for administration of a second dose of vaccine has not been defined. HPIV3-seronegative children between the ages of 6 and 36 months were randomized 2:1 in a blinded study to receive two doses of 10(5) TCID50 (50% tissue culture infectious dose) of live-attenuated, recombinant cold-passaged human PIV3 vaccine (rHPIV3cp45) or placebo 6 months apart. Serum antibody levels were assessed prior to and approximately 4-6 weeks after each dose. Vaccine virus infectivity, defined as detection of vaccine-HPIV3 in nasal wash and/or a≥4-fold rise in serum antibody titer, and reactogenicity were assessed on days 3, 7, and 14 following immunization. Forty HPIV3-seronegative children (median age 13 months; range 6-35 months) were enrolled; 27 (68%) received vaccine and 13 (32%) received placebo. Infectivity was detected in 25 (96%) of 26 evaluable vaccinees following doses 1 and 9 of 26 subject (35%) following dose 2. Among those who shed virus, the median duration of viral shedding was 12 days (range 6-15 days) after dose 1 and 6 days (range 3-8 days) after dose 2, with a mean peak log10 viral titer of 3.4PFU/mL (SD: 1.0) after dose 1 compared to 1.5PFU/mL (SD: 0.92) after dose 2. Overall, reactogenicity was mild, with no difference in rates of fever and upper respiratory infection symptoms between vaccine and placebo groups. rHPIV3cp45 was immunogenic and well-tolerated in seronegative young children. A second dose administered 6 months after the initial dose was restricted in those previously infected with vaccine virus; however, the second dose boosted antibody responses and induced antibody responses in two previously uninfected children.
    Vaccine 10/2013; · 3.49 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A recombinant chimeric bovine/human parainfluenza type 3 virus (rB/HPIV3) vector expressing the respiratory syncytial virus (RSV) fusion F glycoprotein previously exhibited disappointing levels of RSV F immunogenicity and genetic stability in children (Bernstein et al., Pediatr Infect Dis J 2012;31:109-114; Yang et al., Vaccine 2013;31:2822-2827). To investigate parameters that might affect vaccine performance and stability, we constructed and characterized rB/HPIV3 viruses expressing RSV F from the 1(st) (pre-N), 2(nd) (N-P), 3(rd) (P-M), and 6(th) (HN-L) genome positions. There was a 30- to 69-fold gradient in RSV F expression from the 1(st) to the 6(th) position. The inserts moderately attenuated vector replication in vitro and in the upper and lower respiratory tracts (URT, LRT) of hamsters: this was not influenced by the level of RSV F expression and syncytium formation. Surprisingly, inserts in the 2(nd), 3(rd), and 6(th) positions conferred increased temperature-sensitivity: this was greatest for the 3(rd) position and was the most attenuating in vivo. Each rB/HPIV3 vector induced a high titer of neutralizing antibodies in hamsters against RSV and HPIV3. Protection against RSV challenge was greater for position 2 than 6. Evaluation of insert stability suggested that RSV F is under selective pressure to be silenced during vector replication in vivo, but this was not exacerbated by a high level of RSV F expression and generally involved a small percentage of recovered vector. Vector passaged in vitro accumulated mutations in the HN ORF, causing a dramatic increase in plaque size that may have implications for vaccine production and immunogenicity.Importance The research findings presented in this manuscript will be instrumental for improving the design of a bivalent pediatric vaccine for respiratory syncytial virus and parainfluenza virus type 3, two major causes of severe respiratory tract infection in infants and young children. Moreover, this knowledge has general application to the development and clinical evaluation of other mononegavirus vectors and vaccines.
    Journal of Virology 01/2014; · 4.65 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Respiratory syncytial virus (RSV) and human parainfluenza virus type 3 (HPIV-3) are the major causes of lower respiratory tract infection in infants and young children. RSV is also responsible for a significant amount of morbidity and mortality in the elderly, the immunosuppressed and those with chronic cardiac or pulmonary disease. Despite extensive research, no effective antiviral therapy or vaccine is currently available for either virus. Over the past 20 years a number of different approaches for developing vaccines for RSV and HPIV-3 have been tested, with varying degrees of success. However, as it is not yet possible to identify one strategy that yields a vaccine preparation suitable for all high-risk populations, a multi-faceted approach to RSV and HPIV-3 vaccine development is still necessary. Ribavirin and immunoglobulin preparations with high titres of RSV-specific neutralizing antibodies are licensed for the treatment and prevention of RSV infection, but neither is cost-effective or easy to administer. New clinically effective agents are needed to diminish the impact of RSV and HPIV-3. This article will review the currently available means for controlling the two viruses, the search for new antiviral agents, and future prospects for preventing and treating RSV and HPIV-3 infections.
    International Journal of Pharmaceutical Medicine 01/2001; 15(4).

Full-text (2 Sources)

Available from
May 23, 2014