Breaking In: Human Metapneumovirus Fusion and Entry

Cox, Reagan G.; Williams, John V.

doi:10.3390/v5010192

Cited by 30 publications

(24 citation statements)

References 81 publications

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“…The HMPV genome is composed of a negative single stranded RNA molecule of approximately 13 kb in length, containing eight genes encoding for nine different proteins [14,15], including three surface glycoproteins (F, G, SH). The F (fusion) glycoprotein is the major HMPV antigen [16] and leads to both attachment and fusion of viral particles to the target cell [17]. In contrast, the exact role of G (glycoprotein) and SH (small hydrophobic) glycoproteins is still a matter of debate.…”

Section: Introductionmentioning

confidence: 99%

Strain-Dependent Impact of G and SH Deletions Provide New Insights for Live-Attenuated HMPV Vaccine Development

et al. 2019

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Human metapneumovirus (HMPV) is a major pediatric respiratory pathogen with currently no specific treatment or licensed vaccine. Different strategies to prevent this infection have been evaluated, including live-attenuated vaccines (LAV) based on SH and/or G protein deletions. This approach showed promising outcomes but has not been evaluated further using different viral strains. In that regard, we previously showed that different HMPV strains harbor distinct in vitro fusogenic and in vivo pathogenic phenotypes, possibly influencing the selection of vaccine strains. In this study, we investigated the putative contribution of the low conserved SH or G accessory proteins in such strain-dependent phenotypes and generated recombinant wild type (WT) and SH- or G-deleted viruses derived from two different patient-derived HMPV strains, A1/C-85473 and B2/CAN98-75. The ΔSH and ΔG deletions led to different strain-specific phenotypes in both LLC-MK2 cell and reconstituted human airway epithelium models. More interestingly, the ΔG-85473 and especially ΔSH-C-85473 recombinant viruses conferred significant protection against HMPV challenge and induced immunogenicity against a heterologous strain. In conclusion, our results show that the viral genetic backbone should be considered in the design of live-attenuated HMPV vaccines, and that a SH-deleted virus based on the A1/C-85473 HMPV strain could be a promising LAV candidate as it is both attenuated and protective in mice while being efficiently produced in a cell-based system.

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Section: Introductionmentioning

confidence: 99%

Strain-Dependent Impact of G and SH Deletions Provide New Insights for Live-Attenuated HMPV Vaccine Development

et al. 2019

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“…RSV G was also shown to enhance cell-to-cell fusion, in an apparently strainspecific manner (10,13). Similarly, human metapneumovirus (HMPV), another pneumovirus, does not require its G protein for infection (reviewed in reference 14). For both HMPV and RSV, the attachment function of G can be substituted by the F protein (15,16).…”

mentioning

confidence: 99%

Respiratory Syncytial Virus Attachment Glycoprotein Contribution to Infection Depends on the Specific Fusion Protein

Meng

Hotard

Currier

et al. 2016

J Virol

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Human respiratory syncytial virus (RSV) is an important pathogen causing acute lower respiratory tract disease in children. The RSV attachment glycoprotein (G) is not required for infection, as G-null RSV replicates efficiently in several cell lines. Our laboratory previously reported that the viral fusion (F) protein is a determinant of strain-dependent pathogenesis. Here, we hypothesized that virus dependence on G is determined by the strain specificity of F. We generated recombinant viruses expressing G and F, or null for G, from the laboratory A2 strain (Katushka RSV-A2GA2F [kRSV-A2GA2F] and kRSV-GstopA2F) or the clinical isolate A2001/2-20 (kRSV-2-20G2-20F and kRSV-Gstop2-20F). We quantified the virus cell binding, entry kinetics, infectivity, and growth kinetics of these four recombinant viruses in vitro. RSV expressing the 2-20 G protein exhibited the greatest binding activity. Compared to the parental viruses expressing G and F, removal of 2-20 G had more deleterious effects on binding, entry, infectivity, and growth than removal of A2 G. Overall, RSV expressing 2-20 F had a high dependence on G for binding, entry, and infection. IMPORTANCERSV is the leading cause of childhood acute respiratory disease requiring hospitalization. As with other paramyxoviruses, two major RSV surface viral glycoproteins, the G attachment protein and the F fusion protein, mediate virus binding and subsequent membrane fusion, respectively. Previous work on the RSV A2 prototypical strain demonstrated that the G protein is functionally dispensable for in vitro replication. This is in contrast to other paramyxoviruses that require attachment protein function as a prerequisite for fusion. We reevaluated this requirement for RSV using G and F proteins from clinical isolate 2-20. Compared to the laboratory A2 strain, the G protein from 2-20 had greater contributions to virus binding, entry, infectivity, and in vitro growth kinetics. Thus, the clinical isolate 2-20 F protein function depended more on its G protein, suggesting that RSV has a higher dependence on G than previously thought. H uman respiratory syncytial virus (hRSV or RSV) causes an annual global 3.4 million estimated severe acute lower respiratory tract infections (ALRI) in children younger than 5 years of age (1). In the United States, about 132,000 to 172,000 children younger than 5 years of age are hospitalized due to RSV every year (2). Thus far, there are no licensed vaccines, although there are multiple vaccine candidates undergoing clinical trials (3). Development of antivirals against RSV is also an active field of research and clinical development (4-6).RSV is a member of the Paramyxoviridae family, Pneumovirus genus. Members of the paramyxovirus family encode two major glycoproteins important early during infection for attachment to the host cell and the subsequent entry process. Paramyxovirus fusion mediated by the viral fusion (F) protein is generally initiated by interaction with the homologous attachment protein upon receptor engagement (reviewed ...

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“…HMPV is a major viral pathogen in the Egyptian population especially in children. During 2007-2008 with the host cell membrane [5]. The HMPV F protein is a major antigenic determinant which mediates extensive crosslineage neutralization and protection.…”

mentioning

confidence: 99%

Molecular Analysis ofHuman MetapneumovirusDetected in Patients with Lower Respiratory Tract Infection in Upper Egypt

Mohamed

Reiche

Jacobsen

et al. 2014

International Journal of Microbiology

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Introduction. Since 2001, when Human metapneumovirus (HMPV) was isolated in the Netherlands, the virus has been detected in several continents. Although reports have confirmed the prevalence of HMPV worldwide, data from Egypt remain limited. HMPV plays an important role in respiratory tract infections in individuals of all ages particularly in children. This study was aimed at estimating the prevalence of HMPV in patients with community-acquired lower respiratory infection in Upper Egypt and characterizing the circulating Egyptian HMPV strains for the first time. Materials and Methods. From 2005 to 2008, respiratory samples from 520 patients were analyzed for the presence of HMPV by real-time RT-PCR. Molecular and phylogenetic analyses were performed on partial fusion gene sequences of HMPV-positive patients. Results. HMPV-positive patients were detected in 2007-2008. The overall infection rate was 4%, while 57% of the patients were children. Sequence analysis demonstrated circulation of subgroup B viruses with predominance of lineage B2. Nucleotide sequence identity within lineage B1 was 98.8%–99.7% and higher than that in lineage B2 (94.3%–100%). Three new amino acid substitutions (T223N, R229K, and D280N) of lineage B2 were observed. Conclusion. HMPV is a major viral pathogen in the Egyptian population especially in children. During 2007-2008, predominantly HMPV B2 circulated in Upper Egypt.

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Breaking In: Human Metapneumovirus Fusion and Entry

Cited by 30 publications

References 81 publications

Strain-Dependent Impact of G and SH Deletions Provide New Insights for Live-Attenuated HMPV Vaccine Development

Strain-Dependent Impact of G and SH Deletions Provide New Insights for Live-Attenuated HMPV Vaccine Development

Respiratory Syncytial Virus Attachment Glycoprotein Contribution to Infection Depends on the Specific Fusion Protein

Molecular Analysis ofHuman MetapneumovirusDetected in Patients with Lower Respiratory Tract Infection in Upper Egypt

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