scholarly journals Measuring Site-specific Glycosylation Similarity between Influenza a Virus Variants with Statistical Certainty

2020 ◽  
Vol 19 (9) ◽  
pp. 1533-1545
Author(s):  
Deborah Chang ◽  
William E. Hackett ◽  
Lei Zhong ◽  
Xiu-Feng Wan ◽  
Joseph Zaia
Keyword(s):  
Influenza A Virus ◽  
Protein Sequence ◽  
Influenza A ◽  
Viral Fitness ◽  
Antigenic Drift ◽  
Viral Escape ◽  
Strain Selection ◽  
Expression Vectors ◽  
Site Specific ◽  
Measuring Site

Influenza A virus (IAV) mutates rapidly, resulting in antigenic drift and poor year-to-year vaccine effectiveness. One challenge in designing effective vaccines is that genetic mutations frequently cause amino acid variations in IAV envelope protein hemagglutinin (HA) that create new N-glycosylation sequons; resulting N-glycans cause antigenic shielding, allowing viral escape from adaptive immune responses. Vaccine candidate strain selection currently involves correlating antigenicity with HA protein sequence among circulating strains, but quantitative comparison of site-specific glycosylation information may likely improve the ability to design vaccines with broader effectiveness against evolving strains. However, there is poor understanding of the influence of glycosylation on immunodominance, antigenicity, and immunogenicity of HA, and there are no well-tested methods for comparing glycosylation similarity among virus samples. Here, we present a method for statistically rigorous quantification of similarity between two related virus strains that considers the presence and abundance of glycopeptide glycoforms. We demonstrate the strength of our approach by determining that there was a quantifiable difference in glycosylation at the protein level between WT IAV HA from A/Switzerland/9715293/2013 (SWZ13) and a mutant strain of SWZ13, even though no N-glycosylation sequons were changed. We determined site-specifically that WT and mutant HA have varying similarity at the glycosylation sites of the head domain, reflecting competing pressures to evade host immune response while retaining viral fitness. To our knowledge, our results are the first to quantify changes in glycosylation state that occur in related proteins of considerable glycan heterogeneity. Our results provide a method for understanding how changes in glycosylation state are correlated with variations in protein sequence, which is necessary for improving IAV vaccine strain selection. Understanding glycosylation will be especially important as we find new expression vectors for vaccine production, as glycosylation state depends greatly on the host species.

scholarly journals Measuring site-specific glycosylation similarity between influenza A virus variants with statistical certainty

2020 ◽  
Author(s):  
Deborah Chang ◽  
William E. Hackett ◽  
Lei Zhong ◽  
Xiu-Feng Wan ◽  
Joseph Zaia
Keyword(s):  
Influenza A Virus ◽  
Protein Sequence ◽  
Influenza A ◽  
Viral Fitness ◽  
Antigenic Drift ◽  
Viral Escape ◽  
Strain Selection ◽  
Expression Vectors ◽  
Site Specific ◽  
Measuring Site

AbstractInfluenza A virus (IAV) mutates rapidly, resulting in antigenic drift and poor year-to-year vaccine effectiveness. One challenge in designing effective vaccines is that genetic mutations frequently cause amino acid variations in IAV envelope protein hemagglutinin (HA) that create new N-glycosylation sequons; resulting N-glycans cause antigenic shielding, allowing viral escape from adaptive immune responses. Vaccine candidate strain selection currently involves correlating antigenicity with HA protein sequence among circulating strains, but quantitative comparison of site-specific glycosylation information may likely improve the ability to design vaccines with broader effectiveness against evolving strains. However, there is poor understanding of the influence of glycosylation on immunodominance, antigenicity, and immunogenicity of HA, and there are no well-tested methods for comparing glycosylation similarity among virus samples. Here, we present a method for statistically rigorous quantification of similarity between two related virus strains that considers the presence and abundance of glycopeptide glycoforms. We demonstrate the strength of our approach by determining that there was a quantifiable difference in glycosylation at the protein level between wild-type IAV HA from A/Switzerland/9715293/2013 (SWZ13) and a mutant strain of SWZ13, even though no N-glycosylation sequons were changed. We determined site-specifically that WT and mutant HA have varying similarity at the glycosylation sites of the head domain, reflecting competing pressures to evade host immune response while retaining viral fitness. To our knowledge, our results are the first to quantify changes in glycosylation state that occur in related proteins of considerable glycan heterogeneity. Our results provide a method for understanding how changes in glycosylation state are correlated with variations in protein sequence, which is necessary for improving IAV vaccine strain selection. Understanding glycosylation will be especially important as we find new expression vectors for vaccine production, as glycosylation state depends greatly on the host species.

scholarly journals octoFLU: Automated Classification for the Evolutionary Origin of Influenza A Virus Gene Sequences Detected in U.S. Swine

2019 ◽  
Vol 8 (32) ◽  
Author(s):  
Jennifer Chang ◽  
Tavis K. Anderson ◽  
Michael A. Zeller ◽  
Phillip C. Gauger ◽  
Amy L. Vincent
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Antigenic Drift ◽  
Evolutionary Origin ◽  
Automated Classification ◽  
Gene Sequences ◽  
Influenza A Viruses ◽  
Query Gene ◽  
Data Set ◽  
Virus Gene

The diversity of the 8 genes of influenza A viruses (IAV) in swine reflects introductions from nonswine hosts and subsequent antigenic drift and shift. Here, we curated a data set and present a pipeline that assigns evolutionary lineage and genetic clade to query gene segments.

scholarly journals The mechanism of resistance to favipiravir in influenza

2018 ◽  
Vol 115 (45) ◽  
pp. 11613-11618 ◽  
Author(s):  
Daniel H. Goldhill ◽  
Aartjan J. W. te Velthuis ◽  
Robert A. Fletcher ◽  
Pinky Langat ◽  
Maria Zambon ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A Virus ◽  
Influenza A ◽  
H1n1 Influenza ◽  
Viral Fitness ◽  
Virus Infections ◽  
Virus Rna ◽  
Evolution Of Resistance ◽  
Emergence Of Resistance

Favipiravir is a broad-spectrum antiviral that has shown promise in treatment of influenza virus infections. While emergence of resistance has been observed for many antiinfluenza drugs, to date, clinical trials and laboratory studies of favipiravir have not yielded resistant viruses. Here we show evolution of resistance to favipiravir in the pandemic H1N1 influenza A virus in a laboratory setting. We found that two mutations were required for robust resistance to favipiravir. We demonstrate that a K229R mutation in motif F of the PB1 subunit of the influenza virus RNA-dependent RNA polymerase (RdRP) confers resistance to favipiravir in vitro and in cell culture. This mutation has a cost to viral fitness, but fitness can be restored by a P653L mutation in the PA subunit of the polymerase. K229R also conferred favipiravir resistance to RNA polymerases of other influenza A virus strains, and its location within a highly conserved structural feature of the RdRP suggests that other RNA viruses might also acquire resistance through mutations in motif F. The mutations identified here could be used to screen influenza virus-infected patients treated with favipiravir for the emergence of resistance.

scholarly journals Targeting Hemagglutinin: Approaches for Broad Protection against the Influenza A Virus

Viruses ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 405 ◽  
Author(s):  
Zhang ◽  
Xu ◽  
Zhang ◽  
Liu ◽  
Xue ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Protective Efficacy ◽  
Structure And Function ◽  
Antigenic Drift ◽  
Influenza A Viruses ◽  
Universal Vaccine ◽  
Vaccine Candidates ◽  
And Function ◽  
Ha Protein

Influenza A viruses are dynamically epidemic and genetically diverse. Due to the antigenic drift and shift of the virus, seasonal vaccines are required to be reformulated annually to match with current circulating strains. However, the mismatch between vaccinal strains and circulating strains occurs frequently, resulting in the low efficacy of seasonal vaccines. Therefore, several “universal” vaccine candidates based on the structure and function of the hemagglutinin (HA) protein have been developed to meet the requirement of a broad protection against homo-/heterosubtypic challenges. Here, we review recent novel constructs and discuss several important findings regarding the broad protective efficacy of HA-based universal vaccines.

scholarly journals Population-Based Hospitalization Burden of Influenza A Virus Subtypes and Antigenic Drift Variants in Children in Hong Kong (2004–2011)

PLoS ONE ◽  
2014 ◽  
Vol 9 (4) ◽  
pp. e92914 ◽  
Author(s):  
Susan S. Chiu ◽  
Janice Y. C. Lo ◽  
Kwok-Hung Chan ◽  
Eunice L. Y. Chan ◽  
Lok-Yee So ◽  
...  
Keyword(s):  
Hong Kong ◽  
Influenza A Virus ◽  
Influenza A ◽  
Population Based ◽  
Antigenic Drift

scholarly journals A new concept of the epidemic process of influenza A virus

1987 ◽  
Vol 99 (1) ◽  
pp. 5-54 ◽  
Author(s):  
R. E. Hope-Simpson ◽  
D. B. Golubev
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Antigenic Drift ◽  
Current Concept ◽  
World Population ◽  
Human Influenza ◽  
Human Host ◽  
The World ◽  
Antigenic Shift ◽  
Direct Spread

SUMMARYInfluenza A virus was discovered in 1933, and since then four major variants have caused all the epidemies of human influenza A. Each had an era of solo world prevalence until 1977 as follows: H0N1 (old style) strains until 1946. H1N1 (old style) strains until 1957, H2N2 strains until 1968. then H3N2 strains, which were joined in 1977 by a renewed prevalence of H1N1 (old style) strains.Serological studies show that H2N2 strains probably had had a previous era of world prevalence during the last quarter of the nineteenth century, and had then been replaced by H3N2 strains from about 1900 to 1918. From about 1907 the H3N2 strains had been joined, as now. by H1N1 (old style) strains until both had been replaced in 1918 by a fifth major variant closely related to swine influenza virus A/Hswine1N1 (old style), which had then had an era of solo world prevalence in mankind until about 1929. when it had been replaced by the H0N1 strains that were first isolated in 1933.Eras of prevalence of a major variant have usually been initiated by a severe pandemic followed at intervals of a year or two by successive epidemics in each of which the nature of the virus is usually a little changed (antigenic drift), but not enough to permit frequent recurrent infections during the same era. Changes of major variant (antigenic shift) are large enough to permit reinfection. At both major and minor changes the strains of the previous variant tend to disappear and to be replaced within a single season, worldwide in the case of a major variant, or in the area of prevalence of a previous minor variant.Pandemics, epidemics and antigenic variations all occur seasonally, and influenza and its viruses virtually disappear from the population of any locality between epidemics, an interval of many consecutive months. A global view, however, shows influenza continually present in the world population, progressing each year south and then north, thus crossing the equator twice yearly around the equinoxes, the tropical monsoon periods. Influenza arrives in the temperate latitudes in the colder months, about 6 months separating its arrival in the two hemispheres.None of this behaviour is explained by the current concept that the virus is surviving like measles virus by direct spread from the sick providing endless chains of human influenza A. A number of other aspects of the human host influenza A virus relationship encountered in household outbreaks are among the list of 20 difficulties that are inexplicable by the current concept of direct spread.Alternative concepts have usually been designed to counter particular difficulties and are incompatible with other features of influenzal behaviour in mankind. The new concept detailed in the appendix provides simple explanations for most if not all of the difficulties. It proposes that influenza A virus cannot normally be transmitted during the illness because it too rapidly becomes non-infectious in a mode of persistence or latency in the human host. Many months or a year or two later it is reactivated by a seasonally mediated stimulus which, like all seasonal phenomena, is ultimately dependent on variations in solar radiation caused by the tilt of the plane of earth's rotation in relation to that of its circumsolar orbit. The carriers, who are always widely seeded throughout the world population, become briefly infectious and their non-immune companions, if infected, comprise the whole of the next epidemic. The reactivated virus particles must encounter the immunity they have engendered in the carrier, thus allowing minor mutants an advantage over virions identical with the parent virus, and so favouring antigenic drift and automatic disappearance of predecessor and prompt seasonal replacement. Antigenic shift and recycling of major variants may also be explained by virus latency in the human host.

scholarly journals Novel Ranking System for Identifying Efficacious Anti-Influenza Virus PB2 Inhibitors

2015 ◽  
Vol 59 (10) ◽  
pp. 6007-6016 ◽  
Author(s):  
Alice W. Tsai ◽  
Colleen F. McNeil ◽  
Joshua R. Leeman ◽  
Hamilton B. Bennett ◽  
Kwame Nti-Addae ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A Virus ◽  
Influenza A ◽  
Therapeutic Agents ◽  
Influenza Viruses ◽  
Antigenic Drift ◽  
Whole Body ◽  
Infection Model ◽  
Virus Infections

ABSTRACTThrough antigenic drift and shifts, influenza virus infections continue to be an annual cause of morbidity in healthy populations and of death among elderly and at-risk patients. The emergence of highly pathogenic avian influenza viruses such as H5N1 and H7N9 and the rapid spread of the swine-origin H1N1 influenza virus in 2009 demonstrate the continued need for effective therapeutic agents for influenza. While several neuraminidase inhibitors have been developed for the treatment of influenza virus infections, these have shown a limited window for treatment initiation, and resistant variants have been noted in the population. In addition, an older class of antiviral drugs for influenza, the adamantanes, are no longer recommended for treatment due to widespread resistance. There remains a need for new influenza therapeutic agents with improved efficacy as well as an expanded window for the initiation of treatment. Azaindole compounds targeting the influenza A virus PB2 protein and demonstrating excellentin vitroandin vivoproperties have been identified. To evaluate thein vivoefficacy of these PB2 inhibitors, we utilized a mouse influenza A virus infection model. In addition to traditional endpoints, i.e., death, morbidity, and body weight loss, we measured lung function using whole-body plethysmography, and we used these data to develop a composite efficacy score that takes compound exposure into account. This model allowed the rapid identification and ranking of molecules relative to each other and to oseltamivir. The ability to identify compounds with enhanced preclinical properties provides an opportunity to develop more-effective treatments for influenza in patients.

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