scholarly journals Influenza Virus: Small Molecule Therapeutics and Mechanisms of Antiviral Resistance

2019 ◽  
Vol 25 (38) ◽  
pp. 5115-5127 ◽  
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.

scholarly journals Influenza: An Emerging and Re-emerging Public Health Threat in Nepal

2018 ◽  
Vol 3 (2) ◽  
pp. 1-2
Author(s):  
Bishnu Prasad Upadhyay
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Winter Season ◽  
Emerging Infectious Diseases ◽  
Influenza Viruses ◽  
Influenza B ◽  
Influenza A Viruses ◽  
Influenza A H1n1 ◽  
New Variant ◽  
Seasonal Epidemics

Influenza virus type A and B are responsible for seasonal epidemics as well as pandemics in human. Influenza A viruses are further divided into two major groups namely, low pathogenic seasonal influenza (A/H1N1, A/H1N1 pdm09, A/H3N2) and highly pathogenic influenza virus (H5N1, H5N6, H7N9) on the basis of two surface antigens: hemagglutinin (HA) and neuraminidase (NA). Mutations, including substitutions, deletions, and insertions, are one of the most important mechanisms for producing new variant of influenza viruses. During the last 30 years; more than 50 viral threat has been evolved in South-East Asian countriesof them influenza is one of the major emerging and re-emerging infectious diseases of global concern. Similar to tropical and sub-tropical countries of Southeast Asia; circulation of A/H1N1 pdm09, A/H3N2 and influenza B has been circulating throughout the year with the peak during July-November in Nepal. However; the rate of infection transmission reach peak during the post-rain and winter season of Nepal.

Association of Severe Influenza Virus Infections With CD226 (DNAM-1) Variants

2019 ◽  
Vol 220 (7) ◽  
pp. 1162-1165 ◽  
Author(s):  
Monika Redlberger-Fritz ◽  
Hannes Vietzen ◽  
Elisabeth Puchhammer-Stöckl
Keyword(s):  
Influenza Virus ◽  
Intensive Care ◽  
Cell Response ◽  
Nk Cell ◽  
Virus Disease ◽  
Cell Receptor ◽  
Influenza Viruses ◽  
Virus Infections ◽  
Severe Influenza ◽  
Nk Cell Receptor

Abstract Natural killer (NK)-cell response against influenza viruses partly depends on expression of CD112, a ligand for NK-cell receptor CD226 (DNAM-1). We analyzed whether particular CD226 variants were associated with influenza disease severity. Comparison between 145 patients hospitalized with severe influenza at intensive care units (ICU) with 139 matched influenza-positive outpatients showed that presence of the rs763362 G allele (GG, AG) was associated with occurrence of severe influenza infections (P = .0076). Also, a higher frequency of rs727088 G and rs763361 T alleles was observed in the ICU group. Thus, CD226 variants may contribute to the severity of influenza virus disease.

scholarly journals Are Ducks Contributing to the Endemicity of Highly Pathogenic H5N1 Influenza Virus in Asia?

2005 ◽  
Vol 79 (17) ◽  
pp. 11269-11279 ◽  
Author(s):  
K. M. Sturm-Ramirez ◽  
D. J. Hulse-Post ◽  
E. A. Govorkova ◽  
J. Humberd ◽  
P. Seiler ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Virus Disease ◽  
Influenza Viruses ◽  
H5n1 Influenza Virus ◽  
Highly Pathogenic ◽  
Main Site ◽  
H5n1 Influenza ◽  
Pathogenic H5n1 ◽  
Virus Isolates

ABSTRACT Wild waterfowl are the natural reservoir of all influenza A viruses, and these viruses are usually nonpathogenic in these birds. However, since late 2002, H5N1 outbreaks in Asia have resulted in mortality among waterfowl in recreational parks, domestic flocks, and wild migratory birds. The evolutionary stasis between influenza virus and its natural host may have been disrupted, prompting us to ask whether waterfowl are resistant to H5N1 influenza virus disease and whether they can still act as a reservoir for these viruses. To better understand the biology of H5N1 viruses in ducks and attempt to answer this question, we inoculated juvenile mallards with 23 different H5N1 influenza viruses isolated in Asia between 2003 and 2004. All virus isolates replicated efficiently in inoculated ducks, and 22 were transmitted to susceptible contacts. Viruses replicated to higher levels in the trachea than in the cloaca of both inoculated and contact birds, suggesting that the digestive tract is not the main site of H5N1 influenza virus replication in ducks and that the fecal-oral route may no longer be the main transmission path. The virus isolates' pathogenicities varied from completely nonpathogenic to highly lethal and were positively correlated with tracheal virus titers. Nevertheless, the eight virus isolates that were nonpathogenic in ducks replicated and transmitted efficiently to naïve contacts, suggesting that highly pathogenic H5N1 viruses causing minimal signs of disease in ducks can propagate silently and efficiently among domestic and wild ducks in Asia and that they represent a serious threat to human and veterinary public health.

scholarly journals Mutation and Epistasis in Influenza Virus Evolution

Viruses ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 407 ◽  
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.

scholarly journals Age Dependence and Isotype Specificity of Influenza Virus Hemagglutinin Stalk-Reactive Antibodies in Humans

mBio ◽  
2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Raffael Nachbagauer ◽  
Angela Choi ◽  
Ruvim Izikson ◽  
Manon M. Cox ◽  
Peter Palese ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Influenza Virus Infection ◽  
The Elderly ◽  
Influenza Viruses ◽  
Influenza B Virus ◽  
Enzyme Linked Immunosorbent Assay ◽  
Influenza B ◽  
Dependent Manner ◽  
Specific Antibodies

ABSTRACT Influenza remains a major global health burden. Seasonal vaccines offer protection but can be rendered less effective when the virus undergoes extensive antigenic drift. Antibodies that target the highly conserved hemagglutinin stalk can protect against drifted viruses, and vaccine constructs designed to induce such antibodies form the basis for a universal influenza virus vaccine approach. In this study, we analyzed baseline and postvaccination serum samples of children (6 to 59 months), adults (18 to 49 years), and elderly individuals (≥65 years) who participated in clinical trials with a recombinant hemagglutinin-based vaccine. We found that baseline IgG and IgA antibodies against the H1 stalk domain correlated with the ages of patients. Children generally had very low baseline titers and did not respond well to the vaccine in terms of making stalk-specific antibodies. Adults showed the highest induction of stalk-specific antibodies, but the elderly had the highest absolute antibody titers against the stalk. Importantly, the stalk antibodies measured by enzyme-linked immunosorbent assay (ELISA) showed neutralizing activity in neutralization assays and protected mice in a passive-transfer model in a stalk titer-dependent manner. Finally, we found similar patterns of stalk-specific antibodies directed against the H3 and influenza B virus hemagglutinins, albeit at lower levels than those measured against the H1 stalk. The relatively high levels of stalk-specific antibodies in the elderly patients may explain the previously reported low influenza virus infection rates in this age group. (This study has been registered at ClinicalTrials.gov under registration no. NCT00336453, NCT00539981, and NCT00395174.) IMPORTANCE The present study provides evidence that titers of broadly neutralizing hemagglutinin stalk-reactive antibodies increase with age, possibly due to repeated exposure to divergent influenza viruses. These relatively high levels of antistalk titers may be responsible for lower circulation rates of influenza viruses in older individuals. Our findings suggest that the level of antistalk antibodies is a good surrogate marker for protection against influenza virus infection. In addition, the levels of antistalk antibodies might determine the breadth of protection against different drifted strains.

scholarly journals Epidemiological Surveillance of Influenza Virus Matrix Gene in Pigs, in Lagos, Nigeria, 2015-2016

2017 ◽  
Vol 2 (1) ◽  
pp. 1-7
Author(s):  
Abdul-Azeez A. Anjorin ◽  
Olumuyiwa B. Salu ◽  
Akeeb O.B. Oyefolu ◽  
Bamidele O. Oke ◽  
James B. Ayorinde ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A Virus ◽  
Pandemic Influenza ◽  
Influenza A ◽  
Virus Disease ◽  
Influenza Viruses ◽  
Epidemiological Surveillance ◽  
Viral Gene ◽  
Cross Sectional ◽  
Matrix Gene

AbstractThe co-infection of different influenza A virus enable viral gene re-assortments especially in pigs that serve as mixing vessel with the possibility of emergence of novel subtypes. Such re-assortants pose serious public health threat, as epitomised by the emergence of pandemic influenza in 2009. In Nigeria, there is mixture of animal species and highly populated densities that can increase the risk of influenza virus endemicity, genetic reshuffling and emergence of future pandemic influenza viruses. Thus, this study was aimed at determining influenza virus disease burden in pigs. This study was a cross sectional molecular surveillance of influenza virus. A total of 194 pig nasal samples from reported cases and randomly sampled were collected from pig farms in Ojo and Ikorodu in Lagos State between October, 2015 and April, 2016. The samples were investigated for the presence of influenza virus matrix gene by Reverse Transcriptase Polymerase Chain Reaction and detected by gel electrophoresis. P-values were calculated using Chi-square and Fisher’s exact tests. The result showed that 25 (12.9%) samples were positive for influenza A virus, out of which, 20 (80%) were samples from Ojo while 5 (20%) were samples from Ikorodu. Epidemiological parameters for the sampled locations, methods either as reported case or randomised, and sex compared were significant at 95% confidence interval. This study determined influenza viral burden in pigs with a molecular prevalence of 12.9% to influenza A. It further confirmed the sub-clinical and clinical circulation of Influenza A virus in pigs in Ojo and Ikorodu in Lagos. Therefore, the detection of influenza A virus in commercial pigs in Nigeria accentuates the importance of continuous surveillance and monitoring of the virus in order to prevent the advent of virulent strains that may spread to Pig-handlers and the community at large.

scholarly journals Drug-Repositioning Approach for the Discovery of Anti-Influenza Virus Activity of Japanese Herbal (Kampo) Medicines In Vitro: Potent High Activity of Daio-Kanzo-To

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Ken Watanabe
Keyword(s):  
Influenza Virus ◽  
Drug Repositioning ◽  
Antiviral Agents ◽  
Herbal Medicines ◽  
Prescription Medication ◽  
The Elderly ◽  
Influenza Viruses ◽  
Health Concern ◽  
Virus Activity

Influenza virus infections are a serious public health concern throughout the world. Emergence of viral resistance to the currently approved anti-influenza drugs warrants the development of new antiviral agents. Japanese herbal medicines called Kampo are very commonly used as prescription medication in Japan, and Mao-to is known to be effective against influenza that is caused by oseltamivir-resistant viruses. However, influenza-related death occurs mainly among the elderly, and for patients with hypertension and diabetes, Mao-to may cause these diseases to worsen. Therefore, the exploration of more potent and safe Kampo medicines may be a good strategy for developing new influenza medicines. Here cell-based screening of anti-influenza virus activity for 42 approved Kampo medicines was performed using the drug-repositioning approach. As a result, four Kampo medicines were selected as potent anti-influenza agents against the A/WSN/33 strain. It was found that Daio-kanzo-to [50% inhibitory concentration (IC50) = 10.5 μg/mL; 50% cytotoxic concentration (CC50) = 71.6 μg/mL; selective index = 6.8] is more effective than Mao-to. Daio-kanzo-to and its constituent Japanese Pharmacopoeia (JP) Rhubarb were also effective against H3N2 and H1N1 subtypes of influenza viruses, including oseltamivir-insensitive-2009 pandemic clinical isolates. These data suggest the potential application of Daio-kanzo-to for influenza treatment.

scholarly journals High frequency of cross-reacting antibodies against 2009 pandemic influenza A(H1N1) virus among the elderly in Finland

2010 ◽  
Vol 15 (5) ◽  
Author(s):  
N Ikonen ◽  
M Strengell ◽  
L Kinnunen ◽  
P Österlund ◽  
J Pirhonen ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Pandemic Influenza ◽  
Influenza A ◽  
Seasonal Influenza ◽  
H1n1 Virus ◽  
The Elderly ◽  
Influenza Viruses ◽  
Spanish Influenza ◽  
Pandemic Virus ◽  
Influenza A H1n1

Since May 2009, the pandemic influenza A(H1N1) virus has been spreading throughout the world. Epidemiological data indicate that the elderly are underrepresented among the ill individuals. Approximately 1,000 serum specimens collected in Finland in 2004 and 2005 from individuals born between 1909 and 2005, were analysed by haemagglutination-inhibition test for the presence of antibodies against the 2009 pandemic influenza A(H1N1) and recently circulating seasonal influenza A viruses. Ninety-six per cent of individuals born between 1909 and 1919 had antibodies against the 2009 pandemic influenza virus, while in age groups born between 1920 and 1944, the prevalence varied from 77% to 14%. Most individuals born after 1944 lacked antibodies to the pandemic virus. In sequence comparisons the haemagglutinin (HA) gene of the 2009 pandemic influenza A(H1N1) virus was closely related to that of the Spanish influenza and 1976 swine influenza viruses. Based on the three-dimensional structure of the HA molecule, the antigenic epitopes of the pandemic virus HA are more closely related to those of the Spanish influenza HA than to those of recent seasonal influenza A(H1N1) viruses. Among the elderly, cross-reactive antibodies against the 2009 pandemic influenza virus, which likely originate from infections caused by the Spanish influenza virus and its immediate descendants, may provide protective immunity against the present pandemic virus.

scholarly journals Mapping inhibitory sites on the RNA polymerase of the 1918 pandemic influenza virus using nanobodies

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Jeremy R. Keown ◽  
Zihan Zhu ◽  
Loïc Carrique ◽  
Haitian Fan ◽  
Alexander P. Walker ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Rna Polymerase ◽  
Pandemic Influenza ◽  
Influenza A ◽  
Structural Data ◽  
Influenza Viruses ◽  
Viral Rna ◽  
Influenza A Viruses ◽  
Seasonal Epidemics ◽  
1918 Influenza

AbstractInfluenza A viruses cause seasonal epidemics and global pandemics, representing a considerable burden to healthcare systems. Central to the replication cycle of influenza viruses is the viral RNA-dependent RNA polymerase which transcribes and replicates the viral RNA genome. The polymerase undergoes conformational rearrangements and interacts with viral and host proteins to perform these functions. Here we determine the structure of the 1918 influenza virus polymerase in transcriptase and replicase conformations using cryo-electron microscopy (cryo-EM). We then structurally and functionally characterise the binding of single-domain nanobodies to the polymerase of the 1918 pandemic influenza virus. Combining these functional and structural data we identify five sites on the polymerase which are sensitive to inhibition by nanobodies. We propose that the binding of nanobodies at these sites either prevents the polymerase from assuming particular functional conformations or interactions with viral or host factors. The polymerase is highly conserved across the influenza A subtypes, suggesting these sites as effective targets for potential influenza antiviral development.

scholarly journals Novel Small Molecule Targeting the Hemagglutinin Stalk of Influenza Viruses

2019 ◽  
Vol 93 (17) ◽  
Author(s):  
Jin Il Kim ◽  
Sangmoo Lee ◽  
Gong Yeal Lee ◽  
Sehee Park ◽  
Joon-Yong Bae ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Amino Acid ◽  
Membrane Fusion ◽  
Small Molecule ◽  
Screening Method ◽  
Influenza Viruses ◽  
Influenza B ◽  
Challenge Study ◽  
In Cells

ABSTRACTCombating influenza is one of the perennial global public health issues to be managed. Antiviral drugs are useful for the treatment of influenza in the absence of an appropriate vaccine. However, the appearance of resistant strains necessitates a constant search for new drugs. In this study, we investigated novel anti-influenza drug candidates usingin vitroandin vivoassays. We identified anti-influenza hit compounds using a high-throughput screening method with a green fluorescent protein-tagged recombinant influenza virus. Through subsequent analyses of their cytotoxicity and pharmacokinetic properties, one candidate (IY7640) was selected for further evaluation. In a replication kinetics analysis, IY7640 showed greater inhibitory effects during the early phase of viral infection than the viral neuraminidase inhibitor oseltamivir. In addition, we observed that hemagglutinin (HA)-mediated membrane fusion was inhibited by IY7640 treatment, indicating that the HA stalk region, which is highly conserved across various (sub)types of influenza viruses, may be the molecular target of IY7640. In an escape mutant analysis in cells, amino acid mutations were identified at the HA stalk region of the 2009 pandemic H1N1 (pH1N1) virus. Even though thein vivoefficacy of IY7640 did not reach complete protection in a lethal challenge study in mice, these results suggest that IY7640 has potential to be developed as a new type of anti-influenza drug.IMPORTANCEAnti-influenza drugs with broad-spectrum efficacy against antigenically diverse influenza viruses can be highly useful when no vaccines are available. To develop new anti-influenza drugs, we screened a number of small molecules and identified a strong candidate, IY7640. When added at the time of or after influenza virus infection, IY7640 was observed to successfully inhibit or reduce viral replication in cells. We subsequently discovered that IY7640 targets the stalk region of the influenza HA protein, which exhibits a relatively high degree of amino acid sequence conservation across various (sub)types of influenza viruses. Furthermore, IY7640 was observed to block HA-mediated membrane fusion of H1N1, H3N2, and influenza B viruses in cells. Although it appears less effective against strains other than H1N1 subtype viruses in a challenge study in mice, we suggest that the small molecule IY7640 has potential to be optimized as a new anti-influenza drug.

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