A Chimeric Human-Bovine Parainfluenza Virus Type 3 Expressing Measles Virus Hemagglutinin Is Attenuated for Replication but Is Still Immunogenic in Rhesus Monkeys

Skiadopoulos, Mario H.; Surman, Sonja R.; Riggs, Jeffrey M.; Collins, Peter L.; Murphy, Brian R.

doi:10.1128/jvi.75.21.10498-10504.2001

Cited by 22 publications

(8 citation statements)

References 50 publications

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“…This suggests that AMPV has a limited host range. This would be consistent with the experience with HRSV and bovine RSV and human and bovine parainfluenza type 3 virus, which are human/animal counterparts with roughly comparable levels of sequence relatedness and for which each animal counterpart exhibits a strong host range restriction in primates (12,23,32). Conversely, the ability of HMPV to infect birds was tested previously by experimental inoculation of turkeys: during the subsequent 3-week period there was no detectable virus shedding as assayed by RT-PCR of nasal swabs (34).…”

Section: Discussionsupporting

confidence: 65%

Chimeric Recombinant Human Metapneumoviruses with the Nucleoprotein or Phosphoprotein Open Reading Frame Replaced by That of Avian Metapneumovirus Exhibit Improved Growth In Vitro and Attenuation In Vivo

Pham

Biacchesi

Skiadopoulos

et al. 2005

J Virol

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Chimeric versions of recombinant human metapneumovirus (HMPV) were generated by replacing the nucleoprotein (N) or phosphoprotein (P) open reading frame with its counterpart from the closely related avian metapneumovirus (AMPV) subgroup C. In Vero cells, AMPV replicated to an approximately 100-foldhigher titer than HMPV. Surprisingly, the N and P chimeric viruses replicated to a peak titer that was 11-and 25-fold higher, respectively, than that of parental HMPV. The basis for this effect is not known but was not due to obvious changes in the efficiency of gene expression. AMPV and the N and P chimeras were evaluated for replication, immunogenicity, and protective efficacy in hamsters. AMPV was attenuated compared to HMPV in this mammalian host on day 5 postinfection, but not on day 3, and only in the nasal turbinates. In contrast, the N and P chimeras were reduced approximately 100-fold in both the upper and lower respiratory tract on day 3 postinfection, although there was little difference by day 5. The N and P chimeras induced a high level of neutralizing serum antibodies and protective efficacy against HMPV; AMPV was only weakly immunogenic and protective against HMPV challenge, reflecting antigenic differences. In African green monkeys immunized intranasally and intratracheally, the mean peak titer of the P chimera was reduced 100-and 1,000-fold in the upper and lower respiratory tracts, whereas the N chimera was reduced only 10-fold in the lower respiratory tract. Both chimeras were comparable to wild-type HMPV in immunogenicity and protective efficacy. Thus, the P chimera is a promising live HMPV vaccine candidate that paradoxically combines improved growth in vitro with attenuation in vivo.Human metapneumovirus (HMPV) is an enveloped RNA virus of the genus Metapneumovirus, subfamily Pneumovirinae, family Paramyxoviridae, order Mononegavirales. HMPV was first described in 2001 (34) and is now regarded as an important viral respiratory pathogen of worldwide distribution (9,20,35). Its clinical impact warrants the development of a vaccine, particularly for the pediatric population. Avian metapneumovirus (AMPV) is a closely related virus that causes respiratory disease in turkeys, chickens, and other birds (24).HMPV has a nonsegmented negative-strand RNA genome of approximately 13.3 kb that contains eight genes in the order 3Ј-N-P-M-F-M2-SH-G-L-5Ј (5, 33). As is the case for other members of Mononegavirales, the nucleoprotein N, the phosphoprotein P, the RNA-dependent RNA polymerase L, and the viral genomic RNA form the ribonucleoprotein complex, which is the minimal replication/transcription unit. The other genes encode matrix protein M, fusion protein F, M2 mRNA, small hydrophobic glycoprotein SH of unknown function, and putative attachment glycoprotein G. The genomic RNA and its positive-sense replicative intermediate, the antigenomic RNA, are tightly encapsidated by the N protein. The N and L proteins are among the more highly conserved proteins between different Paramyxoviridae species, whereas P is som...

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Section: Discussionsupporting

confidence: 65%

Chimeric Recombinant Human Metapneumoviruses with the Nucleoprotein or Phosphoprotein Open Reading Frame Replaced by That of Avian Metapneumovirus Exhibit Improved Growth In Vitro and Attenuation In Vivo

Pham

Biacchesi

Skiadopoulos

et al. 2005

J Virol

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“…The strategy presented here utilized an attenuated PIV3 virus vector to deliver the hMPV F protein with the aim of inducing both humoral and cell-mediated immunity against hMPV infection. This vectored approach has previously been shown to generate promising hRSV vaccine candidates [18,19] as well as to other respiratory pathogens such as measles virus [36] and the SARS coronavirus [37].…”

Section: Discussionmentioning

confidence: 99%

A host-range restricted parainfluenza virus type 3 (PIV3) expressing the human metapneumovirus (hMPV) fusion protein elicits protective immunity in African green monkeys

Tang¹,

Mahmood²,

MacPhail³

et al. 2005

Vaccine

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Human metapneumovirus (hMPV) infection causes respiratory tract disease similar to that observed during human respiratory syncytial virus infection (hRSV). hMPV infections have been reported across the entire age spectrum although the most severe disease occurs in young children. No vaccines, chemotherapeutics or antibodies are presently available for preventing or treating hMPV infections. In this study, a bovine/human chimeric parainfluenza virus type 3 (b/h PIV3) expressing the human parainfluenza type 3 (hPIV3) fusion (F) and hemagglutinin-neuraminidase (HN) proteins was engineered to express hMPV fusion (F) protein from the second genome position (b/h PIV3/hMPV F2) with the goal of generating a novel hMPV vaccine. b/h PIV3/hMPV F2 was previously shown to protect hamsters from challenge with wt hMPV (Tang RS, Schickli JH, Macphail M, Fernandes F, Bicha L, Spaete J, et al. Effects of human metapneumovirus and respiratory syncytial virus antigen insertion in two 3' proximal genome positions of bovine/human parainfluenza virus type 3 on virus replication and immunogenicity. J Virol 2003;77:10819-28) and is here further evaluated for efficacy and immunogenicity in African green monkeys (AGMs). AGMs immunized intranasally and intratracheally with b/h PIV3/hMPV F2 generated hMPV- and hPIV3-specific humoral and cellular immune responses and were protected from wt hMPV infection. In a separate study, the host-range restriction of b/h PIV3/hMPV F2 replication relative to wt hPIV3 was performed in rhesus monkeys to demonstrate attenuation. These studies showed that b/h PIV3/hMPV F2 was immunogenic, protective and attenuated in non-human primates and warrants further evaluation in humans as a vaccine candidate for prevention of hMPV-associated respiratory tract diseases.

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“…A plethora of live-attenuated viruses and chimeric viruses have been generated using reverse genetics (11,12,22,32,33,35), and the same can now be envisaged for hMPV. For instance, recombinant hMPV strains harboring the surface glycoproteins of both serotype A and B isolates of hMPV can be generated that may induce a broad antibody response in infected hosts.…”

Section: Discussionmentioning

confidence: 99%

Recovery of Human Metapneumovirus Genetic Lineages A and B from Cloned cDNA

Herfst

Graaf

Schickli³

et al. 2004

J Virol

112

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Human metapneumovirus (hMPV) is a newly discovered pathogen associated with respiratory tract illness, primarily in young children, immunocompromised individuals, and the elderly. The genomic sequence of the prototype hMPV isolate NL/1/00 without the terminal leader and trailer sequences has been reported previously. Here we describe the leader and trailer sequences of two hMPV isolates, NL/1/00 and NL/1/99, representing the two main genetic lineages of hMPV. Minigenome constructs in which the green fluorescent protein or chloramphenicol acetyltransferase genes are flanked by the viral genomic ends derived from both hMPV lineages and transcribed using a T7 RNA polymerase promoter-terminator cassette were generated. Cotransfection of minigenome constructs with plasmids expressing the polymerase complex components L, P, N, and M2.1 in 293T or baby hamster kidney cells resulted in expression of the reporter genes. When the minigenome was replaced by a sense or antisense full-length cDNA copy of the NL/1/00 or NL/1/99 viral genomes, recombinant virus was recovered from transfected cells. Viral titers up to 10 7.2 and 10 5.7 50% tissue culture infective dose/ml were achieved with the sense and antisense plasmids, respectively. The recombinant viruses replicated with kinetics similar to those of the parental viruses in Vero cells. This reverse genetics system provides an important new tool for applied and fundamental research.

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A Chimeric Human-Bovine Parainfluenza Virus Type 3 Expressing Measles Virus Hemagglutinin Is Attenuated for Replication but Is Still Immunogenic in Rhesus Monkeys

Cited by 22 publications

References 50 publications

Chimeric Recombinant Human Metapneumoviruses with the Nucleoprotein or Phosphoprotein Open Reading Frame Replaced by That of Avian Metapneumovirus Exhibit Improved Growth In Vitro and Attenuation In Vivo

Chimeric Recombinant Human Metapneumoviruses with the Nucleoprotein or Phosphoprotein Open Reading Frame Replaced by That of Avian Metapneumovirus Exhibit Improved Growth In Vitro and Attenuation In Vivo

A host-range restricted parainfluenza virus type 3 (PIV3) expressing the human metapneumovirus (hMPV) fusion protein elicits protective immunity in African green monkeys

Recovery of Human Metapneumovirus Genetic Lineages A and B from Cloned cDNA

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