Highly pathogenic avian influenza viruses with low virulence for chickens in<i>in vivo</i>tests

Löndt, Brandon Z.; Banks, Jill; Alexander, D. J.

doi:10.1080/03079450701589134

Cited by 47 publications

(43 citation statements)

References 18 publications

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“…The lower clinical score of Hp-H14 poly after oculonasal infection, in contrast to the three other lethal reassortants, suggests that more adaptation would be required. As the IVPIs of Hp-H2 poly , Hp-H4 poly , Hp-H8 poly , and Hp-H14 poly are indistinguishable from those of genuine HPAIV, e.g., the strain A/Chicken/Pennsylvania/1370/83 (H5N2) with an IVPI of 2.37 (23) or the parental Hp-Wt with an IVPI of 2.88 (22,24), our data indicate that non-H5/H7 HA with an engineered polybasic HACS can be functionally equivalent to the HA of natural HPAIV.…”

Section: Discussionmentioning

confidence: 99%

Avian influenza virus hemagglutinins H2, H4, H8, and H14 support a highly pathogenic phenotype

Veits

Weber²,

Stech³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

118

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High-pathogenic avian influenza viruses (HPAIVs) evolve from lowpathogenic precursors specifying the HA serotypes H5 or H7 by acquisition of a polybasic HA cleavage site. As the reason for this serotype restriction has remained unclear, we aimed to distinguish between compatibility of a polybasic cleavage site with H5/H7 HA only and unique predisposition of these two serotypes for insertion mutations. To this end, we introduced a polybasic cleavage site into the HA of several low-pathogenic avian strains with serotypes H1, H2, H3, H4, H6, H8, H10, H11, H14, or H15, and rescued HA reassortants after cotransfection with the genes from either a low-pathogenic H9N2 or high-pathogenic H5N1 strain. Oculonasal inoculation with those reassortants resulted in varying pathogenicity in chicken. Recombinants containing the engineered H2, H4, H8, or H14 in the HPAIV background were lethal and exhibited i.v. pathogenicity indices of 2.79, 2.37, 2.85, and 2.61, respectively, equivalent to naturally occurring H5 or H7 HPAIV. Moreover, the H2, H4, and H8 reassortants were transmitted to some contact chickens. The H2 reassortant gained two mutations in the M2 proton channel gate region, which is affected in some HPAIVs of various origins. Taken together, in the presence of a polybasic HA cleavage site, non-H5/H7 HA can support a highly pathogenic phenotype in the appropriate viral background, indicating requirement for further adaptation. Therefore, the restriction of natural HPAIV to serotypes H5 and H7 is likely a result of their unique predisposition for acquisition of a polybasic HA cleavage site.

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Section: Discussionmentioning

confidence: 99%

Avian influenza virus hemagglutinins H2, H4, H8, and H14 support a highly pathogenic phenotype

Veits

Weber²,

Stech³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

118

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“…To illustrate, a H5N2 virus isolated from a broiler flock and two live bird markets in Texas in 2004 was phenotypically low pathogenic, although possessing the HA 0 cleavage site PQRKKR/ GLF and hence genotypically HPAIV (7). Discordant results between molecular and in vivo tests used to characterize virus patho- genicity were retrospectively recognized for other H5 field virus isolates (8,9), as well as non-H5/H7 viruses that had been engineered to contain polybasic HA 0 cleavage sites (25,26,27). For example Stech et al (26) showed that inserting a polybasic cleavage site identical to that of HPAI A/chicken/Italy/8/98 (H5N2) into the HA of the LPAI A/duck/Ukraine/1/63 (H3N8) virus was not sufficient to immediately transform it into a highly pathogenic virus, despite the fact that it was able to replicate in tissue culture in the absence of exogenous trypsin.…”

Section: Discussionmentioning

confidence: 99%

“…During receptor mediated endocytosis of the virus, a low-pH-induced conformational change of the HA takes place, and this allows the fusion peptide to initiate the merging of the viral envelope with host endosomal membranes, a step necessary for influenza virus infectivity (5). Even though a polybasic HA 0 cleavage site is considered to be the dominant virulence determinant of HPAI H5 and H7 viruses (reviewed in reference 6), there have been instances where it has not been sufficient to confer a highly pathogenic phenotype (7,8,9). This implies that the evolution of a LPAI virus to a HPAI virus must involve additional changes in the other gene segments.…”

Section: Importancementioning

confidence: 99%

Hemagglutinin-Neuraminidase Balance Influences the Virulence Phenotype of a Recombinant H5N3 Influenza A Virus Possessing a Polybasic HA ₀ Cleavage Site

Diederich

Berhane

Embury-Hyatt

et al. 2015

J Virol

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Although a polybasic HA 0 cleavage site is considered the dominant virulence determinant for highly pathogenic avian influenza (HPAI) H5 and H7 viruses, naturally occurring virus isolates possessing a polybasic HA 0 cleavage site have been identified that are low pathogenic in chickens. In this study, we generated a reassortant H5N3 virus that possessed the hemagglutinin (HA) gene from H5N1 HPAI A/swan/Germany/R65/2006 and the remaining gene segments from low pathogenic A/chicken/British Columbia/CN0006/2004 (H7N3). Despite possessing the HA 0 cleavage site GERRRKKR/GLF, this rH5N3 virus exhibited a low pathogenic phenotype in chickens. Although rH5N3-inoculated birds replicated and shed virus and seroconverted, transmission to naive contacts did not occur. To determine whether this virus could evolve into a HPAI form, it underwent six serial passages in chickens. A progressive increase in virulence was observed with the virus from passage number six being highly transmissible. Whole-genome sequencing demonstrated the fixation of 12 nonsynonymous mutations involving all eight gene segments during passaging. One of these involved the catalytic site of the neuraminidase (NA; R293K) and is associated with decreased neuraminidase activity and resistance to oseltamivir. Although introducing the R293K mutation into the original low-pathogenicity rH5N3 increased its virulence, transmission to naive contact birds was inefficient, suggesting that one or more of the remaining changes that had accumulated in the passage number six virus also play an important role in transmissibility. Our findings show that the functional linkage and balance between HA and NA proteins contributes to expression of the HPAI phenotype. IMPORTANCETo date, the contribution that hemagglutinin-neuraminidase balance can have on the expression of a highly pathogenic avian influenza virus phenotype has not been thoroughly examined. Reassortment, which can result in new hemagglutinin-neuraminidase combinations, may have unpredictable effects on virulence and transmission characteristics of a virus. Our data show the importance of the neuraminidase in complementing a polybasic HA 0 cleavage site. Furthermore, it demonstrates that adaptive changes selected for during the course of virus evolution can result in unexpected traits such as antiviral drug resistance.A vian influenza viruses (AIV) belong to the genus Influenzavirus A in the family Orthomyxoviridae. Although wild waterfowl are considered the natural reservoir for all influenza A viruses, sporadic transmission to poultry and mammals can result in viruses that are adapted to a new host. The roles that the different viral genes play in this process, especially as it relates to tropism and virulence for domestic poultry species, are still not well understood.Influenza A viruses contain a negative-sense, single-stranded, eight-segmented RNA genome that codes for at least 11 proteins. Viruses are categorized based on the hemagglutinin (HA) and neuraminidase (NA) envelope glycoproteins. Sixt...

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“…In addition to the HA, the virus polymerase gene complex (PB1, PB2, and PA) and nucleoprotein (NP) also modulate the pathogenicity of AI viruses, as demonstrated for H5N1 HPAI viruses (21)(22)(23). Importantly, the insertion of multiple basic amino acids at the cleavage site is not always sufficient to convert an LPAI virus phenotype into an HPAI one, as demonstrated in experimental studies (24) and sporadically in natural infections (25)(26)(27).…”

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confidence: 99%

Emergence of a Highly Pathogenic Avian Influenza Virus from a Low-Pathogenic Progenitor

Monne

Fusaro

Nelson

et al. 2014

J Virol

131

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Avian influenza (AI) viruses of the H7 subtype have the potential to evolve into highly pathogenic (HP) viruses that represent a major economic problem for the poultry industry and a threat to global health. However, the emergence of HPAI viruses from low-pathogenic (LPAI) progenitor viruses currently is poorly understood. To investigate the origin and evolution of one of the most important avian influenza epidemics described in Europe, we investigated the evolutionary and spatial dynamics of the entire genome of 109 H7N1 (46 LPAI and 63 HPAI) viruses collected during Italian H7N1 outbreaks between March 1999 and February 2001. Phylogenetic analysis revealed that the LPAI and HPAI epidemics shared a single ancestor, that the HPAI strains evolved from the LPAI viruses in the absence of reassortment, and that there was a parallel emergence of mutations among HPAI and later LPAI lineages. Notably, an ultradeep-sequencing analysis demonstrated that some of the amino acid changes characterizing the HPAI virus cluster were already present with low frequency within several individual viral populations from the beginning of the LPAI H7N1 epidemic. A Bayesian phylogeographic analysis revealed stronger spatial structure during the LPAI outbreak, reflecting the more rapid spread of the virus following the emergence of HPAI. The data generated in this study provide the most complete evolutionary and phylogeographic analysis of epidemiologically intertwined high-and low-pathogenicity viruses undertaken to date and highlight the importance of implementing prompt eradication measures against LPAI to prevent the appearance of viruses with fitness advantages and unpredictable pathogenic properties. IMPORTANCEThe Italian H7 AI epidemic of 1999 to 2001 was one of the most important AI outbreaks described in Europe. H7 viruses have the ability to evolve into HP forms from LP precursors, although the mechanisms underlying this evolutionary transition are only poorly understood. We combined epidemiological information, whole-genome sequence data, and ultradeep sequencing approaches to provide the most complete characterization of the evolution of HPAI from LPAI viruses undertaken to date. Our analysis revealed that the LPAI viruses were the direct ancestors of the HPAI strains and identified low-frequency minority variants with HPAI mutations that were present in the LPAI samples. Spatial analysis provided key information for the design of effective control strategies for AI at both local and global scales. Overall, this work highlights the importance of implementing rapid eradication measures to prevent the emergence of novel influenza viruses with severe pathogenic properties.

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Highly pathogenic avian influenza viruses with low virulence for chickens inin vivotests

Cited by 47 publications

References 18 publications

Avian influenza virus hemagglutinins H2, H4, H8, and H14 support a highly pathogenic phenotype

Avian influenza virus hemagglutinins H2, H4, H8, and H14 support a highly pathogenic phenotype

Hemagglutinin-Neuraminidase Balance Influences the Virulence Phenotype of a Recombinant H5N3 Influenza A Virus Possessing a Polybasic HA ₀ Cleavage Site

Emergence of a Highly Pathogenic Avian Influenza Virus from a Low-Pathogenic Progenitor

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Highly pathogenic avian influenza viruses with low virulence for chickens inin vivotests

Cited by 47 publications

References 18 publications

Avian influenza virus hemagglutinins H2, H4, H8, and H14 support a highly pathogenic phenotype

Avian influenza virus hemagglutinins H2, H4, H8, and H14 support a highly pathogenic phenotype

Hemagglutinin-Neuraminidase Balance Influences the Virulence Phenotype of a Recombinant H5N3 Influenza A Virus Possessing a Polybasic HA 0 Cleavage Site

Emergence of a Highly Pathogenic Avian Influenza Virus from a Low-Pathogenic Progenitor

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Hemagglutinin-Neuraminidase Balance Influences the Virulence Phenotype of a Recombinant H5N3 Influenza A Virus Possessing a Polybasic HA ₀ Cleavage Site