Contact transmission of influenza virus between ferrets imposes a looser bottleneck than respiratory droplet transmission allowing propagation of antiviral resistance

The 3D8 single-chain variable fragment (scFv) is a mini-antibody sequence with independent nuclease activity that shows antiviral effects against all types of viruses in chickens and mice. In this study, chickens were treated daily with an oral dose of 109 CFU Lactobacillus paracasei (L. paracasei) expressing either a secreted or anchored 3D8 scFv for three weeks. After L. paracasei administration, the chickens were challenged with avian influenza virus (AIV). From each experimental group, three chickens were directly infected with 100 µL of 107.5 EID50/mL H9N2 AIV and seven chickens were indirectly challenged through contact transmission. oropharyngeal and cloacal swab samples were collected at 3, 5, 7, and 9 days post-inoculation (dpi) from AIV-challenged chickens, AIV Shedding titres were measured by quantitative real-time PCR. Contact transmission in the chickens that were fed 3D8 scFv-secreting L. paracasei showed a significant reduction in viral shedding when compared with other groups. These results suggest that L. paracasei secreting 3D8 provides a basis for the development of ingestible antiviral probiotics with activity against AIV.

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Influenza Virus: Small Molecule Therapeutics and Mechanisms of Antiviral Resistance

Current Medicinal Chemistry ◽

10.2174/0929867324666170920165926 ◽

2019 ◽

Vol 25 (38) ◽

pp. 5115-5127 ◽

Cited By ~ 13

Author(s):

Julianna Han ◽

Jasmine Perez ◽

Adam Schafer ◽

Han Cheng ◽

Norton Peet ◽

...

Keyword(s):

Influenza Virus ◽

Small Molecule ◽

Virus Disease ◽

The Elderly ◽

Significant Loss ◽

Influenza Viruses ◽

Antiviral Resistance ◽

Novel Therapeutics ◽

Seasonal Epidemics ◽

Small Molecule Therapeutics

Background: Influenza viruses cause severe upper respiratory illness in children and the elderly during seasonal epidemics. Influenza viruses from zoonotic reservoirs can also cause pandemics with significant loss of life in all age groups. Although vaccination is one of the most effective methods to protect against seasonal epidemics, seasonal vaccines vary in efficacy, can be ineffective in the elderly population, and do not provide protection against novel strains. Small molecule therapeutics are a critical part of our antiviral strategies to control influenza virus epidemics and pandemics as well as to ameliorate disease in elderly and immunocompromised individuals. Objective: This review aims to summarize the existing antiviral strategies for combating influenza viruses, the mechanisms of antiviral resistance for available drugs, and novel therapeutics currently in development. Methods: We systematically evaluated and synthesized the published scientific literature for mechanistic detail into therapeutic strategies against influenza viruses. Results: Current IAV strains have developed resistance to neuraminidase inhibitors and nearly complete resistance to M2 ion channel inhibitors, exacerbated by sub-therapeutic dosing used for treatment and chemoprophylaxis. New tactics include novel therapeutics targeting host components and combination therapy, which show potential for fighting influenza virus disease while minimizing viral resistance. Conclusion: Antiviral drugs are crucial for controlling influenza virus disease burden, but their efficacy is limited by human misuse and the capacity of influenza viruses to circumvent antiviral barriers. To relieve the public health hardship of influenza virus, emerging therapies must be selected for their capacity to impede not only influenza virus disease, but also the development of antiviral resistance.

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Mutation and Epistasis in Influenza Virus Evolution

Viruses ◽

10.3390/v10080407 ◽

2018 ◽

Vol 10 (8) ◽

pp. 407 ◽

Cited By ~ 26

Author(s):

Daniel Lyons ◽

Adam Lauring

Keyword(s):

Public Health ◽

Influenza Virus ◽

Vaccine Efficacy ◽

Rapid Evolution ◽

Evolutionary Process ◽

Virus Evolution ◽

Influenza Viruses ◽

Antiviral Resistance ◽

Epistatic Interactions ◽

Public Health Challenge

Influenza remains a persistent public health challenge, because the rapid evolution of influenza viruses has led to marginal vaccine efficacy, antiviral resistance, and the annual emergence of novel strains. This evolvability is driven, in part, by the virus’s capacity to generate diversity through mutation and reassortment. Because many new traits require multiple mutations and mutations are frequently combined by reassortment, epistatic interactions between mutations play an important role in influenza virus evolution. While mutation and epistasis are fundamental to the adaptability of influenza viruses, they also constrain the evolutionary process in important ways. Here, we review recent work on mutational effects and epistasis in influenza viruses.

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The antiviral resistance of influenza virus

Therapy ◽

10.2217/thy.11.79 ◽

2011 ◽

Vol 8 (6) ◽

pp. 741-762 ◽

Cited By ~ 3

Author(s):

Vanessa Escuret ◽

Olivier Ferraris ◽

Bruno Lina

Keyword(s):

Influenza Virus ◽

Antiviral Resistance

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Identification of Stabilizing Mutations in an H5 Hemagglutinin Influenza Virus Protein

Journal of Virology ◽

10.1128/jvi.02790-15 ◽

2015 ◽

Vol 90 (6) ◽

pp. 2981-2992 ◽

Cited By ~ 13

Author(s):

Anthony Hanson ◽

Masaki Imai ◽

Masato Hatta ◽

Ryan McBride ◽

Hirotaka Imai ◽

...

Keyword(s):

Influenza Virus ◽

Avian Influenza ◽

Conformational Change ◽

Receptor Binding ◽

Heat Stability ◽

Influenza Viruses ◽

Virus Infectivity ◽

Highly Pathogenic ◽

Human Type ◽

Droplet Transmission

ABSTRACTHighly pathogenic avian influenza viruses of the H5N1 subtype continue to circulate in poultry in Asia, Africa, and the Middle East. Recently, outbreaks of novel reassortant H5 viruses have also occurred in North America. Although the number of human infections with highly pathogenic H5N1 influenza viruses continues to rise, these viruses remain unable to efficiently transmit between humans. However, we and others have identified H5 viruses capable of respiratory droplet transmission in ferrets. Two experimentally introduced mutations in the viral hemagglutinin (HA) receptor-binding domain conferred binding to human-type receptors but reduced HA stability. Compensatory mutations in HA (acquired during virus replication in ferrets) were essential to restore HA stability. These stabilizing mutations in HA also affected the pH at which HA undergoes an irreversible switch to its fusogenic form in host endosomes, a crucial step for virus infectivity. To identify additional stabilizing mutations in an H5 HA, we subjected a virus library possessing random mutations in the ectodomain of an H5 HA (altered to bind human-type receptors) to three rounds of treatment at 50°C. We isolated several mutants that maintained their human-type receptor-binding preference but acquired an appreciable increase in heat stability and underwent membrane fusion at a lower pH; collectively, these properties may aid H5 virus respiratory droplet transmission in mammals.IMPORTANCEWe have identified mutations in HA that increase its heat stability and affect the pH that triggers an irreversible conformational change (a prerequisite for virus infectivity). These mutations were identified in the genetic background of an H5 HA protein that was mutated to bind to human cells. The ability to bind to human-type receptors, together with physical stability and an altered pH threshold for HA conformational change, may facilitate avian influenza virus transmission via respiratory droplets in mammals.

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INFLUENZA VIRUS SURVEILLANCE BY THE INSTITUTO ADOLFO LUTZ, INFLUENZA SEASON 2014: ANTIVIRAL RESISTANCE

Revista do Instituto de Medicina Tropical de São Paulo ◽

10.1590/s0036-46652015000100016 ◽

2015 ◽

Vol 57 (1) ◽

pp. 92-92

Author(s):

Katia Corrêa de Oliveira Santos ◽

Daniela Bernardes Borges da Silva ◽

Margarete Aparecida Benega ◽

Renato de Sousa Paulino ◽

Elian Reis E Silva Jr ◽

...

Keyword(s):

Influenza Virus ◽

Influenza Season ◽

Antiviral Resistance ◽

Virus Surveillance

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The Discovery of the Antiviral Resistance GeneMx: A Story of Great Ideas, Great Failures, and Some Success

Annual Review of Virology ◽

10.1146/annurev-virology-092917-043525 ◽

2018 ◽

Vol 5 (1) ◽

pp. 33-51 ◽

Cited By ~ 8

Author(s):

Otto Haller ◽

Heinz Arnheiter ◽

Jovan Pavlovic ◽

Peter Staeheli

Keyword(s):

Influenza Virus ◽

Antiviral Resistance ◽

Innate Resistance ◽

Interferon Stimulated Genes ◽

Pure Chance ◽

New View

The discovery of the Mx gene–dependent, innate resistance of mice against influenza virus was a matter of pure chance. Although the subsequent analysis of this antiviral resistance was guided by straightforward logic, it nevertheless led us into many blind alleys and was full of surprising turns and twists. Unexpectedly, this research resulted in the identification of one of the first interferon-stimulated genes and provided a new view of interferon action. It also showed that in many species, MX proteins have activities against a broad range of viruses. To this day, Mx research continues to flourish and to provide insights into the never-ending battle between viruses and their hosts.

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