Repositioning Drugs on Human Influenza A Viruses Based on a Novel Nuclear Norm Minimization Method

Influenza A viruses, especially H3N2 and H1N1 subtypes, are viruses that often spread among humans and cause influenza pandemic. There have been several big influenza pandemics that have caused millions of human deaths in history, and the threat of influenza viruses to public health is still serious nowadays due to the frequent antigenic drift and antigenic shift events. However, only few effective anti-flu drugs have been developed to date. The high development cost, long research and development time, and drug side effects are the major bottlenecks, which could be relieved by drug repositioning. In this study, we proposed a novel antiviral Drug Repositioning method based on minimizing Matrix Nuclear Norm (DRMNN). Specifically, a virus-drug correlation database consisting of 34 viruses and 205 antiviral drugs was first curated from public databases and published literature. Together with drug similarity on chemical structure and virus sequence similarity, we formulated the drug repositioning problem as a low-rank matrix completion problem, which was solved by minimizing the nuclear norm of a matrix with a few regularization terms. DRMNN was compared with three recent association prediction algorithms. The AUC of DRMNN in the global fivefold cross-validation (fivefold CV) is 0.8661, and the AUC in the local leave-one-out cross-validation (LOOCV) is 0.6929. Experiments have shown that DRMNN is better than other algorithms in predicting which drugs are effective against influenza A virus. With H3N2 as an example, 10 drugs most likely to be effective against H3N2 viruses were listed, among which six drugs were reported, in other literature, to have some effect on the viruses. The protein docking experiments between the chemical structure of the prioritized drugs and viral hemagglutinin protein also provided evidence for the potential of the predicted drugs for the treatment of influenza.

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A multiplex real-time PCR assay for detection of oseltamivir-resistant strains of influenza virus

Open Life Sciences ◽

10.2478/s11535-014-0296-z ◽

2014 ◽

Vol 9 (6) ◽

pp. 628-633

Author(s):

Dawid Nidzworski ◽

Joanna Dobkowska ◽

Marcin Hołysz ◽

Beata Gromadzka ◽

Bogusław Szewczyk

Keyword(s):

Real Time ◽

Influenza A Virus ◽

Real Time Pcr ◽

Influenza A ◽

Influenza Pandemic ◽

Neuraminidase Inhibitor ◽

Influenza Viruses ◽

Antigenic Drift ◽

Influenza A Viruses ◽

Oseltamivir Resistance

AbstractInfluenza is a contagious disease of humans and animals caused by viruses belonging to the Orthomyxoviridae family. The influenza A virus genome consists of negative sense, single-stranded, segmented RNA. Influenza viruses are classified into subtypes based on two surface antigens known as hemagglutinin (H) and neuraminidase (N). The main problem with influenza A viruses infecting humans is drug resistance, which is caused by antigenic changes. A few antiviral drugs are available, but the most popular is the neuraminidase inhibitor — oseltamivir. The resistance against this drug has probably developed through antigenic drift by a point mutation in one amino acid at position 275 (H275Y). In order to prevent a possible influenza pandemic it is necessary to develop fast diagnostic tests. The aim of this project was to develop a new test for detection of influenza A virus and determination of oseltamivir resistance/sensitivity in humans. Detection and differentiation of oseltamivir resistance/sensitivity of influenza A virus was based on real-time PCR. This test contains two TaqMan probes, which work at different wavelengths. Application of techniques like multiplex real-time PCR has greatly enhanced the capability for surveillance and characterization of influenza viruses. After its potential validation, this test can be used for diagnosis before treatment.

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Divergent Human-Origin Influenza Viruses Detected in Australian Swine Populations

Journal of Virology ◽

10.1128/jvi.00316-18 ◽

2018 ◽

Vol 92 (16) ◽

Cited By ~ 6

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.

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The evolution of human influenza viruses

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2001.0999 ◽

2001 ◽

Vol 356 (1416) ◽

pp. 1861-1870 ◽

Cited By ~ 278

Author(s):

Alan J. Hay ◽

Victoria Gregory ◽

Alan R. Douglas ◽

Yi Pu Lin

Keyword(s):

Influenza A ◽

Influenza Viruses ◽

Antigenic Drift ◽

Influenza B ◽

Mixed Infections ◽

Human Influenza ◽

Influenza A Viruses ◽

Genetic Reassortment ◽

Influenza Ah1n1 ◽

Novel Influenza A

The evolution of influenza viruses results in (i) recurrent annual epidemics of disease that are caused by progressive antigenic drift of influenza A and B viruses due to the mutability of the RNA genome and (ii) infrequent but severe pandemics caused by the emergence of novel influenza A subtypes to which the population has little immunity. The latter characteristic is a consequence of the wide antigenic diversity and peculiar host range of influenza A viruses and the ability of their segmented RNA genomes to undergo frequent genetic reassortment (recombination) during mixed infections. Contrasting features of the evolution of recently circulating influenza AH1N1, AH3N2 and B viruses include the rapid drift of AH3N2 viruses as a single lineage, the slow replacement of successive antigenic variants of AH1N1 viruses and the co–circulation over some 25 years of antigenically and genetically distinct lineages of influenza B viruses. Constant monitoring of changes in the circulating viruses is important for maintaining the efficacy of influenza vaccines in combating disease.

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Serological studies of influenza viruses in pigs in Great Britain 1991–2

Epidemiology and Infection ◽

10.1017/s0950268800052225 ◽

1995 ◽

Vol 114 (3) ◽

pp. 511-520 ◽

Cited By ~ 31

Author(s):

I. H. Brown ◽

P. A. Harris ◽

D. J. Alexander

Keyword(s):

Great Britain ◽

Influenza A ◽

H1n1 Virus ◽

Haemagglutination Inhibition ◽

Influenza Viruses ◽

Antigenic Drift ◽

H3n2 Virus ◽

Influenza B Virus ◽

Influenza B ◽

Influenza A Viruses

SUMMARYSamples from a sow serum bank representative of the pig population of Great Britain collected during 1991–2, were examined for antibodies to influenza A, B and C viruses, using viruses which had been isolated from a variety of hosts. For influenza A viruses there was evidence of the continued circulation of ‘classical swine’ H1N1 virus (26%) seroprevalence), and human H3N2 viruses (39%) which are antigenically most closely-related to A/Port Chalmers/1/73 virus. In addition antibodies were detected to A/swine/England/201635/92 (8%), a strain of H3N2 virus which appears to have arisen by antigenic drift from conventional H3N2 swine strains. Specific antibodies (2%) were detected to an H1N1 virus (A/swine/England/195852/92) related most closely to avian H1N1 strains. In tests with human H1N1 and H3N2 viruses, excluding isolates from pigs, the highest seroprevalence was detected to the prevailing strains from the human population. Serological tests with avian H4 and H10, human H2, equine 1 and 2 influenza A viruses were all negative. Seven pigs seropositive by haemagglutination-inhibition, virus neutralization and immunoblotting assays for antibody to influenza B virus, were randomly distributed geographically suggesting that influenza B viruses may be transmitted to pigs but fail to spread. The seroprevalence to influenza C viruses was 9·9% indicating that these viruses are widespread in pigs. These results provide further evidence that the pig can be infected by a number of influenza viruses, some of which may have significance in the epidemiology of human influenza.

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Preparing intensive care for the next pandemic influenza

Critical Care ◽

10.1186/s13054-019-2616-1 ◽

2019 ◽

Vol 23 (1) ◽

Cited By ~ 33

Author(s):

Taylor Kain ◽

Robert Fowler

Keyword(s):

Resource Allocation ◽

Influenza Virus ◽

Intensive Care ◽

Pandemic Influenza ◽

Influenza A ◽

Large Scale ◽

Influenza Pandemic ◽

Influenza Viruses ◽

Antigenic Drift ◽

Timely Initiation

Abstract Few viruses have shaped the course of human history more than influenza viruses. A century since the 1918–1919 Spanish influenza pandemic—the largest and deadliest influenza pandemic in recorded history—we have learned much about pandemic influenza and the origins of antigenic drift among influenza A viruses. Despite this knowledge, we remain largely underprepared for when the next major pandemic occurs. While emergency departments are likely to care for the first cases of pandemic influenza, intensive care units (ICUs) will certainly see the sickest and will likely have the most complex issues regarding resource allocation. Intensivists must therefore be prepared for the next pandemic influenza virus. Preparation requires multiple steps, including careful surveillance for new pandemics, a scalable response system to respond to surge capacity, vaccine production mechanisms, coordinated communication strategies, and stream-lined research plans for timely initiation during a pandemic. Conservative models of a large-scale influenza pandemic predict more than 170% utilization of ICU-level resources. When faced with pandemic influenza, ICUs must have a strategy for resource allocation as strain increases on the system. There are several current threats, including avian influenza A(H5N1) and A(H7N9) viruses. As humans continue to live in closer proximity to each other, travel more extensively, and interact with greater numbers of birds and livestock, the risk of emergence of the next pandemic influenza virus mounts. Now is the time to prepare and coordinate local, national, and global efforts.

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UBIQUITOUS REASSORTMENTS IN INFLUENZA A VIRUSES

Journal of Bioinformatics and Computational Biology ◽

10.1142/s0219720008003813 ◽

2008 ◽

Vol 06 (05) ◽

pp. 981-999 ◽

Cited By ~ 3

Author(s):

XIU-FENG WAN ◽

MUFIT OZDEN ◽

GUOHUI LIN

Keyword(s):

Influenza A ◽

Matrix Protein ◽

Minimum Spanning Tree ◽

Migratory Birds ◽

Rna Virus ◽

Influenza Pandemic ◽

Influenza Viruses ◽

Influenza A Viruses ◽

H5n1 Avian Influenza Virus ◽

Pandemic Strains

The influenza A virus is a negative-stranded RNA virus composed of eight segmented RNA molecules, including polymerases (PB2, PB1, PA), hemagglutinin (HA), nucleoprotein (NP), neuraminidase (NA), matrix protein (MP), and nonstructure gene (NS). The influenza A viruses are notorious for rapid mutations, frequent reassortments, and possible recombinations. Among these evolutionary events, reassortments refer to exchanges of discrete RNA segments between co-infected influenza viruses, and they have facilitated the generation of pandemic and epidemic strains. Thus, identification of reassortments will be critical for pandemic and epidemic prevention and control. This paper presents a reassortment identification method based on distance measurement using complete composition vector (CCV) and segment clustering using a minimum spanning tree (MST) algorithm. By applying this method, we identified 34 potential reassortment clusters among 2,641 PB2 segments of influenza A viruses. Among the 83 serotypes tested, at least 56 (67.46%) exchanged their fragments with another serotype of influenza A viruses. These identified reassortments involve 1,957 H2N1 and 1,968 H3N2 influenza pandemic strains as well as H5N1 avian influenza virus isolates, which have generated the potential for a future pandemic threat. More frequent reassortments were found to occur in wild birds, especially migratory birds. This MST clustering program is written in Java and will be available upon request.

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Induction of Virus-Specific Cytotoxic T Lymphocytes as a Basis for the Development of Broadly Protective Influenza Vaccines

Journal of Biomedicine and Biotechnology ◽

10.1155/2011/939860 ◽

2011 ◽

Vol 2011 ◽

pp. 1-12 ◽

Cited By ~ 58

Author(s):

Marine L. B. Hillaire ◽

Albert D. M. E. Osterhaus ◽

Guus F. Rimmelzwaan

Keyword(s):

T Lymphocytes ◽

Influenza A Virus ◽

Cytotoxic T Lymphocytes ◽

Influenza A ◽

Influenza Viruses ◽

Antigenic Drift ◽

Influenza Vaccines ◽

Virus Infections ◽

Influenza A Viruses ◽

Heterosubtypic Immunity

There is considerable interest in the development of broadly protective influenza vaccines because of the continuous emergence of antigenic drift variants of seasonal influenza viruses and the threat posed by the emergence of antigenically distinct pandemic influenza viruses. It has been recognized more than three decades ago that influenza A virus-specific cytotoxic T lymphocytes recognize epitopes located in the relatively conserved proteins like the nucleoprotein and that they cross-react with various subtypes of influenza A viruses. This implies that these CD8+T lymphocytes may contribute to protective heterosubtypic immunity induced by antecedent influenza A virus infections. In the present paper, we review the evidence for the role of virus-specific CD8+T lymphocytes in protective immunity against influenza virus infections and discuss vaccination strategies that aim at the induction of cross-reactive virus-specific T-cell responses.

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B Cell Responses against Influenza Viruses: Short-Lived Humoral Immunity against a Life-Long Threat

Viruses ◽

10.3390/v13060965 ◽

2021 ◽

Vol 13 (6) ◽

pp. 965

Author(s):

Jenna J. Guthmiller ◽

Henry A. Utset ◽

Patrick C. Wilson

Keyword(s):

B Cells ◽

Humoral Immunity ◽

Influenza A ◽

Neutralizing Antibody ◽

Memory B Cells ◽

Influenza Viruses ◽

Antigenic Drift ◽

Virus Infections ◽

Influenza A Viruses ◽

Major Surface

Antibodies are critical for providing protection against influenza virus infections. However, protective humoral immunity against influenza viruses is limited by the antigenic drift and shift of the major surface glycoproteins, hemagglutinin and neuraminidase. Importantly, people are exposed to influenza viruses throughout their life and tend to reuse memory B cells from prior exposure to generate antibodies against new variants. Despite this, people tend to recall memory B cells against constantly evolving variable epitopes or non-protective antigens, as opposed to recalling them against broadly neutralizing epitopes of hemagglutinin. In this review, we discuss the factors that impact the generation and recall of memory B cells against distinct viral antigens, as well as the immunological limitations preventing broadly neutralizing antibody responses. Lastly, we discuss how next-generation vaccine platforms can potentially overcome these obstacles to generate robust and long-lived protection against influenza A viruses.

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Oseltamivir susceptibility in south-western France during the 2007-8 and 2008-9 influenza epidemics and the ongoing influenza pandemic 2009

Eurosurveillance ◽

10.2807/ese.14.38.19334-en ◽

2009 ◽

Vol 14 (38) ◽

Cited By ~ 4

Author(s):

S Burrel ◽

L Roncin ◽

M E Lafon ◽

H Fleury

Keyword(s):

Influenza A ◽

Seasonal Influenza ◽

Influenza Pandemic ◽

Influenza Viruses ◽

Neuraminidase Inhibitors ◽

Influenza A Viruses ◽

Oseltamivir Resistance ◽

The Past ◽

Influenza A H1n1 ◽

Recent Emergence

The recent emergence of seasonal influenza A(H1N1) strains resistant to oseltamivir makes it necessary to monitoring carefully the susceptibility of human influenza viruses to neuraminidase inhibitors. We report the prevalence of the oseltamivir resistance among influenza A viruses circulating in south-western France over the past three years: seasonal influenza A(H1N1), seasonal influenza A(H3N2), and the influenza A(H1N1)v viruses associated with the ongoing 2009 pandemic. The main result of the study is the absence of oseltamivir resistance in the pandemic H1N1 strains studied so far (n=129).

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Protective porcine influenza virus-specific monoclonal antibodies recognize similar haemagglutinin epitopes as humans

PLoS Pathogens ◽

10.1371/journal.ppat.1009330 ◽

2021 ◽

Vol 17 (3) ◽

pp. e1009330

Author(s):

Barbara Holzer ◽

Pramila Rijal ◽

Adam McNee ◽

Basudev Paudyal ◽

Veronica Martini ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Influenza A ◽

Virus Evolution ◽

Influenza Viruses ◽

Antigenic Drift ◽

Lung Pathology ◽

Influenza A Viruses ◽

Vaccine Recommendations ◽

Natural Hosts ◽

Zoonotic Strains

Pigs are natural hosts for the same subtypes of influenza A viruses as humans and integrally involved in virus evolution with frequent interspecies transmissions in both directions. The emergence of the 2009 pandemic H1N1 virus illustrates the importance of pigs in evolution of zoonotic strains. Here we generated pig influenza-specific monoclonal antibodies (mAbs) from H1N1pdm09 infected pigs. The mAbs recognized the same two major immunodominant haemagglutinin (HA) epitopes targeted by humans, one of which is not recognized by post-infection ferret antisera that are commonly used to monitor virus evolution. Neutralizing activity of the pig mAbs was comparable to that of potent human anti-HA mAbs. Further, prophylactic administration of a selected porcine mAb to pigs abolished lung viral load and greatly reduced lung pathology but did not eliminate nasal shedding of virus after H1N1pdm09 challenge. Hence mAbs from pigs, which target HA can significantly reduce disease severity. These results, together with the comparable sizes of pigs and humans, indicate that the pig is a valuable model for understanding how best to apply mAbs as therapy in humans and for monitoring antigenic drift of influenza viruses in humans, thereby providing information highly relevant to making influenza vaccine recommendations.

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