scholarly journals Large-Scale Sequence Analysis of M Gene of Influenza A Viruses from Different Species: Mechanisms for Emergence and Spread of Amantadine Resistance

2009 ◽  
Vol 53 (10) ◽  
pp. 4457-4463 ◽  
Author(s):  
Yuki Furuse ◽  
Akira Suzuki ◽  
Hitoshi Oshitani
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Drug Resistant ◽  
Human Influenza ◽  
Influenza A Viruses ◽  
M Gene ◽  
Drug Pressure ◽  
Human Influenza Virus ◽  
Selective Pressures ◽  
Amantadine Resistance

ABSTRACT Influenza A virus infects many species, and amantadine is used as an antiviral agent. Recently, a substantial increase in amantadine-resistant strains has been reported, most of which have a substitution at amino acid position 31 in the M2 gene. Understanding the mechanism responsible for the emergence and spread of antiviral resistance is important for developing a treatment protocol for seasonal influenza and for deciding on a policy for antiviral stockpiling for pandemic influenza. The present study was conducted to identify the existence of drug pressure on the emergence and spread of amantadine-resistant influenza A viruses. We analyzed data on more than 5,000 virus sequences and constructed a phylogenetic tree to calculate selective pressures on sites in the M2 gene associated with amantadine resistance (positions 26, 27, 30, and 31) among different hosts. The phylogenetic tree revealed that the emergence and spread of the drug-resistant M gene in different hosts and subtypes were independent and not through reassortment. For human influenza virus, positive selection was detected only at position 27. Selective pressures on the sites were not always higher for human influenza virus than for viruses of other hosts. Additionally, selective pressure on position 31 did not increase after the introduction of amantadine. Although there is a possibility of drug pressure on human influenza virus, we could not find positive pressure on position 31. Because the recent rapid increase in drug-resistant virus is associated with the substitution at position 31, the resistance may not be related to drug use.

scholarly journals Cooperation between the Hemagglutinin of Avian Viruses and the Matrix Protein of Human Influenza A Viruses

2002 ◽  
Vol 76 (4) ◽  
pp. 1781-1786 ◽  
Author(s):  
Christoph Scholtissek ◽  
Jürgen Stech ◽  
Scott Krauss ◽  
Robert G. Webster
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Matrix Protein ◽  
Gene Products ◽  
Human Influenza ◽  
Influenza A Viruses ◽  
M Gene ◽  
Human Virus ◽  
Ha Gene ◽  
M Proteins

ABSTRACT To analyze the compatibility of avian influenza A virus hemagglutinins (HAs) and human influenza A virus matrix (M) proteins M1 and M2, we doubly infected Madin-Darby canine kidney cells with amantadine (1-aminoadamantane hydrochloride)-resistant human viruses and amantadine-sensitive avian strains. By using antisera against the human virus HAs and amantadine, we selected reassortants containing the human virus M gene and the avian virus HA gene. In our system, high virus yields and large, well-defined plaques indicated that the avian HAs and the human M gene products could cooperate effectively; low virus yields and small, turbid plaques indicated that cooperation was poor. The M gene products are among the primary components that determine the species specificities of influenza A viruses. Therefore, our system also indicated whether the avian HA genes effectively reassorted into the genome and replaced the HA gene of the prevailing human influenza A viruses. Most of the avian HAs that we tested efficiently cooperated with the M gene products of the early human A/PR/8/34 (H1N1) virus; however, the avian HAs did not effectively cooperate with the most recently isolated human virus that we tested, A/Nanchang/933/95 (H3N2). Cooperation between the avian HAs and the M proteins of the human A/Singapore/57 (H2N2) virus was moderate. These results suggest that the currently prevailing human influenza A viruses might have lost their ability to undergo antigenic shift and therefore are unable to form new pandemic viruses that contain an avian HA, a finding that is of great interest for pandemic planning.

scholarly journals Divergent Human-Origin Influenza Viruses Detected in Australian Swine Populations

2018 ◽  
Vol 92 (16) ◽  
Author(s):  
Frank Y. K. Wong ◽  
Celeste Donato ◽  
Yi-Mo Deng ◽  
Don Teng ◽  
Naomi Komadina ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Swine Influenza ◽  
Influenza Viruses ◽  
Antigenic Drift ◽  
Human Origin ◽  
Human Influenza ◽  
Influenza A Viruses ◽  
Data Set ◽  
Antigenic Properties

ABSTRACTGlobal swine populations infected with influenza A viruses pose a persistent pandemic risk. With the exception of a few countries, our understanding of the genetic diversity of swine influenza viruses is limited, hampering control measures and pandemic risk assessment. Here we report the genomic characteristics and evolutionary history of influenza A viruses isolated in Australia from 2012 to 2016 from two geographically isolated swine populations in the states of Queensland and Western Australia. Phylogenetic analysis with an expansive human and swine influenza virus data set comprising >40,000 sequences sampled globally revealed evidence of the pervasive introduction and long-term establishment of gene segments derived from several human influenza viruses of past seasons, including the H1N1/1977, H1N1/1995, H3N2/1968, and H3N2/2003, and the H1N1 2009 pandemic (H1N1pdm09) influenza A viruses, and a genotype that contained gene segments derived from the past three pandemics (1968, reemerged 1977, and 2009). Of the six human-derived gene lineages, only one, comprising two viruses isolated in Queensland during 2012, was closely related to swine viruses detected from other regions, indicating a previously undetected circulation of Australian swine lineages for approximately 3 to 44 years. Although the date of introduction of these lineages into Australian swine populations could not be accurately ascertained, we found evidence of sustained transmission of two lineages in swine from 2012 to 2016. The continued detection of human-origin influenza virus lineages in swine over several decades with little or unpredictable antigenic drift indicates that isolated swine populations can act as antigenic archives of human influenza viruses, raising the risk of reemergence in humans when sufficient susceptible populations arise.IMPORTANCEWe describe the evolutionary origins and antigenic properties of influenza A viruses isolated from two separate Australian swine populations from 2012 to 2016, showing that these viruses are distinct from each other and from those isolated from swine globally. Whole-genome sequencing of virus isolates revealed a high genotypic diversity that had been generated exclusively through the introduction and establishment of human influenza viruses that circulated in past seasons. We detected six reassortants with gene segments derived from human H1N1/H1N1pdm09 and various human H3N2 viruses that circulated during various periods since 1968. We also found that these swine viruses were not related to swine viruses collected elsewhere, indicating independent circulation. The detection of unique lineages and genotypes in Australia suggests that isolated swine populations that are sufficiently large can sustain influenza virus for extensive periods; we show direct evidence of a sustained transmission for at least 4 years between 2012 and 2016.

scholarly journals Variation at Extra-epitopic Amino Acid Residues Influences Suppression of Influenza Virus Replication by M158-66 Epitope-Specific CD8+ T Lymphocytes

2018 ◽  
Vol 92 (11) ◽  
pp. e00232-18 ◽  
Author(s):  
Carolien E. van de Sandt ◽  
Mark R. Pronk ◽  
Carel A. van Baalen ◽  
Ron A. M. Fouchier ◽  
Guus F. Rimmelzwaan
Keyword(s):  
Influenza Virus ◽  
T Lymphocytes ◽  
Virus Replication ◽  
Influenza A ◽  
Gene Segment ◽  
Influenza Viruses ◽  
Amino Acid Residues ◽  
Human Influenza ◽  
M Gene ◽  
Specific Ctls

ABSTRACT Influenza virus-specific CD8+ T lymphocytes (CTLs) contribute to clearance of influenza virus infections and reduce disease severity. Variation at amino acid residues located in or outside CTL epitopes has been shown to affect viral recognition by virus-specific CTLs. In the present study, we investigated the effect of naturally occurring variation at residues outside the conserved immunodominant and HLA*0201-restricted M158-66 epitope, located in the influenza virus M1 protein, on the extent of virus replication in the presence of CTLs specific for the epitope. To this end, we used isogenic viruses with an M1 gene segment derived from either an avian or a human influenza virus, HLA-transgenic human epithelial cells, human T cell clones specific for the M158-66 epitope or a control epitope, and a novel, purposely developed in vitro system to coculture influenza virus-infected cells with T cells. We found that the M gene segment of a human influenza A/H3N2 virus afforded the virus the capacity to replicate better in the presence of M158-66-specific CTLs than the M gene segment of avian viruses. These findings are in concordance with previously observed differential CTL activation, caused by variation at extra-epitopic residues, and may reflect an immune adaptation strategy of human influenza viruses that allows them to cope with potent CTL immunity to the M158-66 epitope in HLA-A*0201-positive individuals, resulting in increased virus replication and shedding and possibly increasing disease severity. IMPORTANCE Influenza viruses are among the leading causes of acute respiratory tract infections. CD8+ T lymphocytes display a high degree of cross-reactivity with influenza A viruses of various subtypes and are considered an important correlate of protection. Unraveling viral immune evasion strategies and identifying signs of immune adaptation are important for defining the role of CD8+ T lymphocytes in affording protection more accurately. Improving our insight into the interaction between influenza viruses and virus-specific CD8+ T lymphocyte immunity may help to advance our understanding of influenza virus epidemiology, aid in risk assessment of potentially pandemic influenza virus strains, and benefit the design of vaccines that induce more broadly protective immunity.

scholarly journals Overexpression of the α-2,6-Sialyltransferase in MDCK Cells Increases Influenza Virus Sensitivity to Neuraminidase Inhibitors

2003 ◽  
Vol 77 (15) ◽  
pp. 8418-8425 ◽  
Author(s):  
Mikhail Matrosovich ◽  
Tatyana Matrosovich ◽  
Jackie Carr ◽  
Noel A. Roberts ◽  
Hans-Dieter Klenk
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Cultured Cells ◽  
Mdck Cells ◽  
Sialic Acids ◽  
Neuraminidase Inhibitors ◽  
Human Influenza ◽  
Oseltamivir Carboxylate ◽  
Human Influenza Virus ◽  
Human Virus

ABSTRACT No reliable cell culture assay is currently available for monitoring human influenza virus sensitivity to neuraminidase inhibitors (NAI). This can be explained by the observation that because of a low concentration of sialyl-α2,6-galactose (Sia[α2,6]Gal)-containing virus receptors in conventional cell lines, replication of human virus isolates shows little dependency on viral neuraminidase. To test whether overexpression of Sia(α2,6)Gal moieties in cultured cells could make them suitable for testing human influenza virus sensitivity to NAI, we stably transfected MDCK cells with cDNA of human 2,6-sialyltransferase (SIAT1). Transfected cells expressed twofold-higher amounts of 6-linked sialic acids and twofold-lower amounts of 3-linked sialic acids than parent MDCK cells as judged by staining with Sambucus nigra agglutinin and Maackia amurensis agglutinin, respectively. After transfection, binding of a clinical human influenza virus isolate was increased, whereas binding of its egg-adapted variant which preferentially bound 3-linked receptors was decreased. The sensitivity of human influenza A and B viruses to the neuraminidase inhibitor oseltamivir carboxylate was substantially improved in the SIAT1-transfected cell line and was consistent with their sensitivity in neuraminidase enzyme assay and with the hemagglutinin (HA) receptor-binding phenotype. MDCK cells stably transfected with SIAT1 may therefore be a suitable system for testing influenza virus sensitivity to NAI.

scholarly journals Characterization of Drug-Resistant Influenza Virus A(H1N1) and A(H3N2) Variants SelectedIn Vitrowith Laninamivir

2014 ◽  
Vol 58 (9) ◽  
pp. 5220-5228 ◽  
Author(s):  
Mélanie Samson ◽  
Yacine Abed ◽  
François-Marc Desrochers ◽  
Stephanie Hamilton ◽  
Angela Luttick ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Solomon Islands ◽  
The United States ◽  
Drug Resistant ◽  
Virus Infections ◽  
Influenza A Viruses ◽  
Oseltamivir Resistance ◽  
Susceptibility Profiles

ABSTRACTNeuraminidase inhibitors (NAIs) play a major role for managing influenza virus infections. The widespread oseltamivir resistance among 2007-2008 seasonal A(H1N1) viruses and community outbreaks of oseltamivir-resistant A(H1N1)pdm09 strains highlights the need for additional anti-influenza virus agents. Laninamivir is a novel long-lasting NAI that has demonstratedin vitroactivity against influenza A and B viruses, and its prodrug (laninamivir octanoate) is in phase II clinical trials in the United States and other countries. Currently, little information is available on the mechanisms of resistance to laninamivir. In this study, we first performed neuraminidase (NA) inhibition assays to determine the activity of laninamivir against a set of influenza A viruses containing NA mutations conferring resistance to one or many other NAIs. We also generated drug-resistant A(H1N1) and A(H3N2) viruses underin vitrolaninamivir pressure. Laninamivir demonstrated a profile of susceptibility that was similar to that of zanamivir. More specifically, it retained activity against oseltamivir-resistant H275Y and N295S A(H1N1) variants and the E119V A(H3N2) variant.In vitro, laninamivir pressure selected the E119A NA substitution in the A/Solomon Islands/3/2006 A(H1N1) background, whereas E119K and G147E NA changes along with a K133E hemagglutinin (HA) substitution were selected in the A/Quebec/144147/2009 A(H1N1)pdm09 strain. In the A/Brisbane/10/2007 A(H3N2) background, a large NA deletion accompanied by S138A/P194L HA substitutions was selected. This H3N2 variant had altered receptor-binding properties and was highly resistant to laninamivir in plaque reduction assays. Overall, we confirmed the similarity between zanamivir and laninamivir susceptibility profiles and demonstrated that both NA and HA changes can contribute to laninamivir resistancein vitro.

Long-term survival of influenza A viruses in aquatic invertebrate zoocultures

2021 ◽  
Vol 1 (3) ◽  
pp. 34-41
Author(s):  
S. L. Nesterchuk ◽  
◽  
V. A. Ostapenko ◽  
Keyword(s):  
Influenza Virus ◽  
Daphnia Magna ◽  
Influenza A Virus ◽  
Influenza A ◽  
The Body ◽  
Aquatic Invertebrate ◽  
Human Influenza ◽  
Influenza A Viruses ◽  
Term Survival ◽  
Chicken Embryos

In experiments to infect aquatic invertebrates in the zooculture, we used influenza A viruses, namely, to infect crustaceans Daphnia magna Straus, 1826 – human influenza virus, Hong Kong strain 1569/79 (H3N2), and to infect molluscs Anodonta cygnea Linné, 1758 – influenza virus A birds, Strain Rostok 1/34 (Hav1Neq1) – the so-called true bird plague virus. As a result of a series of experiments, found that influenza A viruses persist in the water for no more than 3 days, while in the gills and mantle of molluscs the virus is isolated on chicken embryos for at least another 35 days after contact with virus-containing water (a total of 70 individuals were studied). From the body Daphnia magna, to isolate the human influenza A virus on chicken embryos was possible within 14 days after infection through water (examined 6,800 individuals), by the method of immunofluorescence the influenza virus was determined in the intestines of crustaceans during the entire period of observation – 70 days from the time of infection. Influenza A viruses do not have a harmful effect on crustaceans or molluscs, infected animals also develop and reproduce, as well as individuals of control groups. Interesting is the fact that we have established the possibility of the loss of agglutination of red blood cells of chickens as a result of the reproduction of the human influenza A virus in the body of invertebrate Daphnia magna, which indicates a change in the viral protein hemagglutinin. The use of aquatic invertebrate zooculture can help in the study of the circulation of influenza A viruses in nature, as well as in the study of the variability of influenza A viruses.

scholarly journals Sulphatide binds to human and animal influenza A viruses, and inhibits the viral infection

1996 ◽  
Vol 318 (2) ◽  
pp. 389-393 ◽  
Author(s):  
Takashi SUZUKI ◽  
Ayako SOMETANI ◽  
Yasuhiro YAMAZAKI ◽  
Goh HORIIKE ◽  
Yukiko MIZUTANI ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A Virus ◽  
Influenza A ◽  
Sialic Acid Residue ◽  
Influenza A Viruses ◽  
Human Influenza Virus ◽  
Viral Binding ◽  
Overlay Assay ◽  
Virus Isolates ◽  
Darby Canine Kidney

We found, by using a virus overlay assay, that influenza A virus isolates bind to sulphatide (HSO3-Galβ1 → 1´Cer), which has no sialic acid residue, and that the infection of Madin–Darby canine kidney cells with the human influenza virus A/Memphis/1/71 (H3N2) is inhibited by sulphatide. A/Memphis/1/71 (H3N2) causes obvious haemagglutination and low-pH haemolysis of asialoerythrocytes reconstituted with sulphatide. All influenza A virus isolates from the species of animals so far tested bound to sulphatide. The sulphatide-binding specificity of the isolates was different from the viral sialyl-linkage specificity. Influenza A virus isolates also bound to galactosyl ceramide (GalCer; Galβ1 → 1´Cer), as well as sulphatide, in the virus overlay assays. In contrast, the influenza virus did not bind to N-deacyl, a derivative of sulphatide, glucosyl ceramide or the other neutral glycolipids tested. These results indicate that the linkage of galactose, or sulphated galactose, to ceramide is important for viral binding.

scholarly journals Intranasal Immunization with a Formalin-Inactivated Human Influenza A Virus Whole-Virion Vaccine Alone and Intranasal Immunization with a Split-Virion Vaccine with Mucosal Adjuvants Show Similar Levels of Cross-Protection

2012 ◽  
Vol 19 (7) ◽  
pp. 979-990 ◽  
Author(s):  
Shigefumi Okamoto ◽  
Sumiko Matsuoka ◽  
Nobuyuki Takenaka ◽  
Ahmad M. Haredy ◽  
Takeshi Tanimoto ◽  
...  
Keyword(s):  
Immune Response ◽  
Influenza Virus ◽  
Influenza A ◽  
Protective Efficacy ◽  
Cross Protection ◽  
Human Influenza ◽  
Human Influenza Virus ◽  
Mucosal Adjuvant ◽  
Intranasal Immunization ◽  
The Cross

ABSTRACTThe antigenicity of seasonal human influenza virus changes continuously; thus, a cross-protective influenza vaccine design needs to be established. Intranasal immunization with an influenza split-virion (SV) vaccine and a mucosal adjuvant induces cross-protection; however, no mucosal adjuvant has been assessed clinically. Formalin-inactivated intact human and avian viruses alone (without adjuvant) induce cross-protection against the highly pathogenic H5N1 avian influenza virus. However, it is unknown whether seasonal human influenza formalin-inactivated whole-virion (WV) vaccine alone induces cross-protection against strains within a subtype or in a different subtype of human influenza virus. Furthermore, there are few reports comparing the cross-protective efficacy of the WV vaccine and SV vaccine-mucosal adjuvant mixtures. Here, we found that the intranasal human influenza WV vaccine alone induced both the innate immune response and acquired immune response, resulting in cross-protection against drift variants within a subtype of human influenza virus. The cross-protective efficacy conferred by the WV vaccine in intranasally immunized mice was almost the same as that conferred by a mixture of SV vaccine and adjuvants. The level of cross-protective efficacy was correlated with the cross-reactive neutralizing antibody titer in the nasal wash and bronchoalveolar fluids. However, neither the SV vaccine with adjuvant nor the WV vaccine induced cross-reactive virus-specific cytotoxic T-lymphocyte activity. These results suggest that the intranasal human WV vaccine injection alone is effective against variants within a virus subtype, mainly through a humoral immune response, and that the cross-protection elicited by the WV vaccine and the SV vaccine plus mucosal adjuvants is similar.

scholarly journals Emergence and Characterization of a Novel Reassortant Canine Influenza Virus Isolated from Cats

Pathogens ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1320
Author(s):  
Jin Zhao ◽  
Wanting He ◽  
Meng Lu ◽  
Haijian He ◽  
Alexander Lai
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Influenza Viruses ◽  
Influenza A Viruses ◽  
Reassortant Virus ◽  
Human Influenza Virus ◽  
Canine Influenza Virus ◽  
Stray Cats ◽  
Wide Range ◽  
Canine Influenza

Cats are susceptible to a wide range of influenza A viruses (IAV). Furthermore, cats can serve as an intermediate host, and transfer avian influenza virus (AIV) H7N2 to a veterinarian. In this report, a novel reassortant influenza virus, designated A/feline/Jiangsu/HWT/2017 (H3N2), and abbreviated as FIV-HWT-2017, was isolated from nasal swab of a symptomatic cat in Jiangsu province, China. Sequence analysis indicated that, whilst the other seven genes were most similar to the avian-origin canine influenza viruses (CIV H3N2) isolated in China, the NS gene was more closely related to the circulating human influenza virus (H3N2) in the region. Therefore, FIV-HWT-2017 is a reassortant virus. In addition, some mutations were identified, and they were similar to a distinctive CIV H3N2 clade. Whether these cats were infected with the reassortant virus was unknown, however, this random isolation of a reassortant virus indicated that domestic or stray cats were “mixing vessel” for IAV cannot be ruled out. An enhanced surveillance for novel influenza virus should include pet and stray cats.

scholarly journals Influenza Virus Protecting RNA: an Effective Prophylactic and Therapeutic Antiviral

2008 ◽  
Vol 82 (17) ◽  
pp. 8570-8578 ◽  
Author(s):  
Nigel J. Dimmock ◽  
Edward W. Rainsford ◽  
Paul D. Scott ◽  
Anthony C. Marriott
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Influenza Pandemic ◽  
Therapeutic Benefit ◽  
Virus Infections ◽  
Influenza A Viruses ◽  
Lethal Challenge ◽  
Human Influenza Virus ◽  
Challenge Virus ◽  
Virus Rna

ABSTRACT Another influenza pandemic is inevitable, and new measures to combat this and seasonal influenza are urgently needed. Here we describe a new concept in antivirals based on a defined, naturally occurring defective influenza virus RNA that has the potential to protect against any influenza A virus in any animal host. This “protecting RNA” (244 RNA) is incorporated into virions which, although noninfectious, deliver the RNA to those cells of the respiratory tract that are naturally targeted by infectious influenza virus. A 120-ng intranasal dose of this 244 protecting virus completely protected mice against a simultaneous challenge of 10 50% lethal doses with influenza A/WSN (H1N1) virus. The 244 virus also protected mice against strong challenge doses of all other subtypes tested (i.e., H2N2, H3N2, and H3N8). This prophylactic activity was maintained in the animal for at least 1 week prior to challenge. The 244 virus was 10- to 100-fold more active than previously characterized defective influenza A viruses, and the protecting activity was confirmed to reside in the 244 RNA molecule by recovering a protecting virus entirely from cloned cDNA. There was a clear therapeutic benefit when the 244 virus was administered 24 to 48 h after a lethal challenge, an effect which has not been previously observed with any defective virus. Protecting virus reduced, but did not abolish, replication of challenge virus in mouse lungs during both prophylactic and therapeutic treatments. Protecting virus is a novel antiviral, having the potential to combat human influenza virus infections, particularly when the infecting strain is not known or is resistant to antiviral drugs.

Sign in / Sign up

Export Citation Format

Share Document