scholarly journals Novel Mutations Evading Avian Immunity around the Receptor Binding Site of the Clade 2.3.2.1c Hemagglutinin Gene Reduce Viral Thermostability and Mammalian Pathogenicity

Viruses ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 923 ◽  
Author(s):  
An ◽  
Lee ◽  
Hong ◽  
Song ◽  
Kim ◽  
...  
Keyword(s):  
Binding Site ◽  
Receptor Binding ◽  
Mammalian Cells ◽  
Influenza A ◽  
Receptor Binding Site ◽  
Receptor Affinity ◽  
Replication Efficiency ◽  
Adaptive Mutations ◽  
H5n1 Avian Influenza ◽  
Clade 2.3.2.1C

Abstract: Since 2007, highly pathogenic clade 2.3.2 H5N1 avian influenza A (A(H5N1)) viruses have evolved to clade 2.3.2.1a, b, and c; currently only 2.3.2.1c A(H5N1) viruses circulate in wild birds and poultry. During antigenic evolution, clade 2.3.2.1a and c A(H5N1) viruses acquired both S144N and V223I mutations around the receptor binding site of hemagglutinin (HA), with S144N generating an N-glycosylation sequon. We introduced single or combined reverse mutations, N144S and/or I223V, into the HA gene of the clade 2.3.2.1c A(H5N1) virus and generated PR8-derived, 2 + 6 recombinant A(H5N1) viruses. When we compared replication efficiency in embryonated chicken eggs, mammalian cells, and mice, the recombinant virus containing both N144S and I223V mutations showed increased replication efficiency in avian and mammalian hosts and pathogenicity in mice. The N144S mutation significantly decreased avian receptor affinity and egg white inhibition, but not all mutations increased mammalian receptor affinity. Interestingly, the combined reverse mutations dramatically increased the thermostability of HA. Therefore, the adaptive mutations possibly acquired to evade avian immunity may decrease viral thermostability as well as mammalian pathogenicity.

scholarly journals Novel Mutations Evading Avian Immunity around the Receptor Binding Site of the Clade 2.3.2.1c Hemagglutinin Gene Reduce Viral Thermostability and Mammalian Pathogenicity

2019 ◽  
Author(s):  
Se-Hee An ◽  
Chung-Young Lee ◽  
Seung-Min Hong ◽  
Chang-Seon Song ◽  
Jae-Hong Kim ◽  
...  
Keyword(s):  
Binding Site ◽  
Receptor Binding ◽  
Mammalian Cells ◽  
Influenza A ◽  
Receptor Binding Site ◽  
Receptor Affinity ◽  
Replication Efficiency ◽  
Adaptive Mutations ◽  
H5n1 Avian Influenza ◽  
Clade 2.3.2.1C

Since 2007, highly pathogenic clade 2.3.2 H5N1 avian influenza A [A(H5N1)] viruses have evolved to clade 2.3.2.1a, b and c, and currently only 2.3.2.1c A(H5N1) viruses circulate in wild birds and poultry. During antigenic evolution, clade 2.3.2.1a and c A(H5N1) viruses acquired both S144N and V223I mutations around the receptor binding site of hemagglutinin (HA), with S144N generating an N-glycosylation sequon. We introduced single or combined reverse mutations, N144S and/or I223V, into the HA gene of clade 2.3.2.1c A(H5N1) virus and generated PR8-derived, 2 + 6 recombinant A(H5N1) viruses. When we compared replication efficiency in embryonated chicken eggs, mammalian cells and mice, the recombinant virus containing both N144S and I223V mutations showed increased replication efficiency in avian and mammalian hosts and pathogenicity in mice. The N144S mutation significantly decreased avian receptor affinity and egg white inhibition, but not all mutations increased mammalian receptor affinity. Interestingly, the combined reverse mutations dramatically increased the thermostability of HA. Therefore, the adaptive mutations possibly acquired to evade avian immunity may decrease viral thermostability as well as mammalian pathogenicity.

scholarly journals Potent sialic acid inhibitors that target influenza A virus hemagglutinin

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yu-Jen Chang ◽  
Cheng-Yun Yeh ◽  
Ju-Chien Cheng ◽  
Yu-Qi Huang ◽  
Kai-Cheng Hsu ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Antiviral Activity ◽  
Binding Site ◽  
Influenza A Virus ◽  
Receptor Binding ◽  
Influenza A ◽  
The United States ◽  
Ligand Complex ◽  
Receptor Binding Site ◽  
Computational Strategy

AbstractEradicating influenza A virus (IAV) is difficult, due to its genetic drift and reassortment ability. As the infectious cycle is initiated by the influenza glycoprotein, hemagglutinin (HA), which mediates the binding of virions to terminal sialic acids moieties, HA is a tempting target of anti-influenza inhibitors. However, the complexity of the HA structure has prevented delineation of the structural characterization of the HA protein–ligand complex. Our computational strategy efficiently analyzed > 200,000 records of compounds held in the United States National Cancer Institute (NCI) database and identified potential HA inhibitors, by modeling the sialic acid (SA) receptor binding site (RBS) for the HA structure. Our modeling revealed that compound NSC85561 showed significant antiviral activity against the IAV H1N1 strain with EC50 values ranging from 2.31 to 2.53 µM and negligible cytotoxicity (CC50 > 700 µM). Using the NSC85561 compound as the template to generate 12 derivatives, robust bioassay results revealed the strongest antiviral efficacies with NSC47715 and NSC7223. Virtual screening clearly identified three SA receptor binding site inhibitors that were successfully validated in experimental data. Thus, our computational strategy has identified SA receptor binding site inhibitors against HA that show IAV-associated antiviral activity.

scholarly journals Substitutions near the Hemagglutinin Receptor-Binding Site Determine the Antigenic Evolution of Influenza A H3N2 Viruses in U.S. Swine

2014 ◽  
Vol 88 (9) ◽  
pp. 4752-4763 ◽  
Author(s):  
N. S. Lewis ◽  
T. K. Anderson ◽  
P. Kitikoon ◽  
E. Skepner ◽  
D. F. Burke ◽  
...  
Keyword(s):  
Binding Site ◽  
Receptor Binding ◽  
Influenza A ◽  
Receptor Binding Site ◽  
Antigenic Evolution

scholarly journals Avian Influenza A Viruses Differ from Human Viruses by Recognition of Sialyloligosaccharides and Gangliosides and by a Higher Conservation of the HA Receptor-Binding Site

Virology ◽  
1997 ◽  
Vol 233 (1) ◽  
pp. 224-234 ◽  
Author(s):  
M.N. Matrosovich ◽  
A.S. Gambaryan ◽  
S. Teneberg ◽  
V.E. Piskarev ◽  
S.S. Yamnikova ◽  
...  
Keyword(s):  
Avian Influenza ◽  
Binding Site ◽  
Receptor Binding ◽  
Influenza A ◽  
Influenza A Viruses ◽  
Receptor Binding Site ◽  
Human Viruses

scholarly journals Novel Monoclonal Antibody Directed at the Receptor Binding Site on the Avian Sarcoma and Leukosis Virus Env Complex

2002 ◽  
Vol 76 (15) ◽  
pp. 7518-7527 ◽  
Author(s):  
Christina Ochsenbauer-Jambor ◽  
Sue E. Delos ◽  
Mary Ann Accavitti ◽  
Judith M. White ◽  
Eric Hunter
Keyword(s):  
Monoclonal Antibody ◽  
Binding Site ◽  
Receptor Binding ◽  
Mammalian Cells ◽  
Leukemia Virus ◽  
Glycosylation Site ◽  
Enzyme Linked Immunosorbent Assay ◽  
Receptor Binding Site ◽  
Avian Sarcoma

ABSTRACT We report here on the generation of a mouse monoclonal antibody directed against Rous sarcoma virus (RSV) subgroup A Env that will be useful in functional and structural analysis of RSV Env, as well as in approaches employing the RCAS/Tva system for gene targeting. BALB/c mice were primed and given boosters twice with EnvA-expressing NIH 3T3 cells. Resulting hybridomas were tested by enzyme-linked immunosorbent assay against RCANBP virions and SU-A-immunoglobulin G immunoadhesin. One highly reactive hybridoma clone, mc8C5, was subcloned and tested in immunofluorescence, immunoprecipitation (IP), and Western blotting assays. In all three assays, mc8C5-4 subgroup-specifically recognizes SR-A Env, through the SU domain, expressed from different vectors in both avian and mammalian cells. This multifunctionality is notable for a mouse monoclonal. We furthermore observed a preference for binding to terminally glycosylated Env over core-glycosylated Env precursor in IPs, suggesting that the epitope is at least partially conformational and dependent on glycosylation. Most importantly, we found mc8C5-4 inhibited Env function: in vitro, the monoclonal not only interferes with binding of the EnvA receptor, Tva, but it also blocks the Tva-induced conformational change required for activation of the fusion peptide, without inducing that change itself. Infection of Tva-expressing avian or mammalian cells by avian sarcoma and leukosis virus (ASLV) or EnvA-pseudotyped murine leukemia virus, respectively, is efficiently inhibited by mc8C5-4. The apparent interference of the monoclonal with the EnvA-Tva complex formation suggests that the epitope seen by mc8C5 overlaps with the receptor binding site. This is supported by the observation that mutations of basic residues in hr2 or of the downstream glycosylation site, which both impair Tva-binding to EnvA, have similar effects on the binding of mc8C5. Thus, anti-ASLV-SU-A mc8C5-4 proves to be a unique new immunoreagent that targets the receptor-binding site on a prototypical retroviral envelope.

scholarly journals Inactivation of influenza virus haemagglutinin by chlorine dioxide: oxidation of the conserved tryptophan 153 residue in the receptor-binding site

2012 ◽  
Vol 93 (12) ◽  
pp. 2558-2563 ◽  
Author(s):  
Norio Ogata
Keyword(s):  
Influenza Virus ◽  
Binding Site ◽  
Receptor Binding ◽  
Chlorine Dioxide ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
Life Time ◽  
Tryptophan Residue ◽  
Dependent Manner ◽  
Receptor Binding Site

Airborne influenza virus infection of mice can be prevented by gaseous chlorine dioxide (ClO2). This study demonstrated that ClO2 abolished the function of the haemagglutinin (HA) of influenza A virus (H1N1) in a concentration-, time- and temperature-dependent manner. The IC50 during a 2 min reaction with ClO2 at 25 °C was 13.7 µM, and the half-life time of HA with 100 µM ClO2 at 25 °C was 19.5 s. Peptides generated from a tryptic digest of ClO2-treated virus were analysed by mass spectrometry. An HA fragment, 150NLLWLTGK157 was identified in which the tryptophan residue (W153) was 32 mass units greater than expected. The W153 residue of this peptide, which is derived from the central region of the receptor-binding site of HA, is highly conserved. It was shown that W153 was oxidized to N-formylkynurenine in ClO2-treated virus. It was concluded that the inactivation of influenza virus by ClO2 is caused by oxidation of W153 in HA, thereby abolishing its receptor-binding ability.

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