#AZT acts as an anti- #influenza nucleotide triphosphate targeting the catalytic site of A/PR/8/34/ #H1N1 RNA dependent RNA #polymerase (J Comput Aided Mol Des., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

J Comput Aided Mol Des. 2019 Feb 9. doi: 10.1007/s10822-019-00189-w. [Epub ahead of print]

AZT acts as an anti-influenza nucleotide triphosphate targeting the catalytic site of A/PR/8/34/H1N1 RNA dependent RNA polymerase.

Pagadala NS1,2,3,4.

Author information: 1 Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, Canada. nattu251@gmail.com. 2 Li Ka Shing Applied Virology Institute, University of Alberta, Edmonton, AB, Canada. nattu251@gmail.com. 3 Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada. nattu251@gmail.com. 4 Medical Microbiology and Immunology, Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, T6G 2E1, Canada. nattu251@gmail.com.

 

Abstract

To develop potent drugs that inhibit the activity of influenza virus RNA dependent RNA polymerase (RdRp), a set of compounds favipiravir, T-705, T-1105 and T-1106, ribavirin, ribavirin triphosphate viramidine, 2FdGTP (2′-deoxy-2′-fluoroguanosine triphosphate) and AZT-TP (3′-Azido-3′-deoxy-thymidine-5′-triphosphate) were docked with a homology model of IAV RdRp from the A/PR/8/34/H1N1 strain. These compounds bind to four pockets A-D of the IAV RdRp with different mechanism of action. In addition, AZT-TP also binds to the PB1 catalytic site near to the tip of the priming loop with a highest ΔG of - 16.7 Kcal/mol exhibiting an IC50 of 1.12 µM in an in vitro enzyme transcription assay. This shows that AZT-TP mainly prevents the incorporation of incoming nucleotide involved in initiation of vRNA replication. Conversely, 2FdGTP used as a positive control binds to pocket-B at the end of tunnel-II with a highest ΔG of - 16.3 Kcal/mol inhibiting chain termination with a similar IC50 of 1.12 µM. Overall, our computational results in correlation with experimental studies gives information for the first time about the binding modes of the known influenza antiviral compounds in different models of vRNA replication by IAV RdRp. This in turn gives new structural insights for the development of new therapeutics exhibiting high specificity to the PB1 catalytic site of influenza A viruses.

KEYWORDS: Catalytic site; Docking; Nucleotide triphosphates; RNA dependent RNA polymerase

PMID: 30739239 DOI: 10.1007/s10822-019-00189-w

Keywords: Influenza A; H1N1; Antivirals; AZT; Ribavirin; Favipiravir.

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Assessing the protective potential of #H1N1 #influenza virus #hemagglutinin head and stalk #antibodies in humans (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

Assessing the protective potential of H1N1 influenza virus hemagglutinin head and stalk antibodies in humans

Shannon R. Christensen, Sushila A. Toulmin, Trevor Griesman, Lois E. Lamerato, Joshua G. Petrie, Emily T. Martin, Arnold S. Monto, Scott E. Hensley

DOI: 10.1128/JVI.02134-18

 

ABSTRACT

Seasonal influenza viruses are a major cause of human disease worldwide. Most neutralizing antibodies (Abs) elicited by influenza viruses target the head domain of the hemagglutinin (HA) protein. Anti-HA head Abs can be highly potent, but they have limited breadth since the HA head is variable. There is great interest in developing new universal immunization strategies that elicit broadly neutralizing Abs against conserved regions of HA, such as the stalk domain. Although HA stalk Abs can provide protection in animal models, it is unknown if they are present at sufficient levels in humans to provide protection against naturally-acquired influenza virus infections. Here, we quantified H1N1 HA head and stalk-specific Abs in 179 adults hospitalized during the 2015-2016 influenza virus season. We found that HA head Abs, as measured by hemagglutinin-inhibition (HAI) assays, were associated with protection against naturally-acquired H1N1 infection. HA stalk-specific serum total IgG titers were also associated with protection, but this association was attenuated and not statistically significant after adjustment for HA head-specific Ab titers. We found slightly higher titers of HA stalk-specific IgG1 and IgA Abs in sera from uninfected participants compared to sera from infected participants; however, we found no difference in sera in vitro antibody dependent cellular cytotoxicity activity. In passive transfer experiments, sera from participants with high HAI activity efficiently protected mice, while sera with low HAI activity protected mice to a lower extent. Our data suggest that HA head Abs are more efficient at protecting against H1N1 infection compared to HA stalk Abs.

 

IMPORTANCE

Abs targeting the HA head of influenza viruses are often associated with protection from influenza virus infections. These Abs typically have limited breadth since mutations frequently arise in HA head epitopes. New vaccines targeting the more conserved HA stalk domain are being developed. Abs that target the HA stalk are protective in animal models, but it is unknown if these Abs exist at protective levels in humans. Here, we completed experiments to determine if Abs against the HA head and stalk were associated with protection from naturally-acquired human influenza virus infections during the 2015-2016 influenza season.

Copyright © 2019 Christensen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords: Influenza A; Seasonal Influenza; H1N1; Serotherapy.

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On the #Centenary of the #SpanishFlu: Being Prepared for the Next #Pandemic (Virol Sin., summary)

[Source: Virologica Sinica, full page: (LINK). Summary, edited.]

On the Centenary of the Spanish Flu: Being Prepared for the Next Pandemic

Authors and affiliations: William J. Liu, Yuhai Bi, Dayan Wang, George F. Gao

First Online: 20 December 2018

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Influenza is one of the oldest infectious diseases affecting humans. Every influenza pandemic in history has ended with disastrous outcomes regarding public health and the social economy. This year marks the 100th anniversary of the Spanish flu (H1N1) outbreak of 1918, which is recognized as the most lethal natural event in recent history. In spite of limited travel and transportation at that time, the Spanish flu pandemic of 1918 reached peak activity on multiple continents simultaneously within several months after its emergence in late 1917 from different hypothesized origins, such as US military camps, the state of Kansas, or the troop staging and hospital camp in Étaples, France (Patterson and Pyle 1991; Oxford et al. 2005; Shanks 2016). However, in some islands of the Pacific region, such as in New Caledonia, the pandemic’s lethal effects lasted for over 3 years, until July 1921 (Shanks et al. 2018). The pandemic flu is estimated to have infected more than 500 million people,…

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Acknowledgements

We are grateful to Drs. Zijian Feng, Zijun Wang, Zhongjie Li, Luzhao Feng, and Tao Chen for their excellent suggestions on the preparation of the figure in this manuscript. This work was supported by the National Key Research and Development Program of China (grant 2017YFC1200202), the Major Special Projects for Infectious Disease Research of China (grant 2016ZX10004222-003), the National Natural Science Foundation of China (grants 81401312 and 81373141). William J. Liu is supported by the Excellent Young Scientist Program of the NSFC (81822040). George F. Gao is a leading principal investigator of the National Natural Science Foundation of China Innovative Research Group (grant 81621091).

Conflict of interest

The authors declare that they have no conflict of interest.

Animal and Human Rights Statement

This article does not contain any studies with human or animal subjects performed by any of the authors.

Keywords: Pandemic Influenza; Influenza A; H1N1; Spanish Flu.

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Predicting #antigenic #variants of #H1N1 #influenza virus based on #epidemics and #pandemics using a stacking model (PLoS One, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

PLoS One. 2018 Dec 21;13(12):e0207777. doi: 10.1371/journal.pone.0207777. eCollection 2018.

Predicting antigenic variants of H1N1 influenza virus based on epidemics and pandemics using a stacking model.

Yin R1, Tran VH2, Zhou X1, Zheng J1,3, Kwoh CK1.

Author information: 1 School of Computer Science and Engineering, Nanyang Technological University, Singapore, Singapore. 2 School of Information and Communication Technology, Hanoi University of Science and Technology, Hanoi, Vietnam. 3 Genome Institute of Singapore, A*STAR, Biopolis, Singapore, Singapore.

 

Abstract

H1N1 is the earliest emerging subtype of influenza A viruses with available genomic sequences, has caused several pandemics and seasonal epidemics, resulting in millions of deaths and enormous economic losses. Timely determination of new antigenic variants is crucial for the vaccine selection and flu prevention. In this study, we chronologically divided the H1N1 strains into several periods in terms of the epidemics and pandemics. Computational models have been constructed to predict antigenic variants based on epidemic and pandemic periods. By sequence analysis, we demonstrated the diverse mutation patterns of HA1 protein on different periods and that an individual model built upon each period can not represent the variations of H1N1 virus. A stacking model was established for the prediction of antigenic variants, combining all the variation patterns across periods, which would help assess a new influenza strain’s antigenicity. Three different feature extraction methods, i.e. residue-based, regional band-based and epitope region-based, were applied on the stacking model to verify its feasibility and robustness. The results showed the capability of determining antigenic variants prediction with accuracy as high as 0.908 which performed better than any of the single models. The prediction performance using the stacking model indicates clear distinctions of mutation patterns and antigenicity between epidemic and pandemic strains. It would also facilitate rapid determination of antigenic variants and influenza surveillance.

PMID: 30576319 DOI: 10.1371/journal.pone.0207777

Keywords: Influenza A; H1N1.

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#Influenza #Cataclysm, 1918 (N Engl J Med., summary)

[Source: The New England Journal of Medicine, full page: (LINK). Summary, edited.]

Influenza Cataclysm, 1918

David M. Morens, M.D., and Jeffery K. Taubenberger, M.D., Ph.D.

December 13, 2018 / N Engl J Med 2018; 379:2285-2287 / DOI: 10.1056/NEJMp1814447

 

Audio Interview

Interview with Dr. David Morens on lessons from the 1918 influenza pandemic and the threat of a similar global health disaster. 

This year marks the centennial of an influenza pandemic that killed 50 million to 100 million people globally — arguably the single deadliest event in recorded human history. Evidence suggests that another pandemic at least as severe may occur one day.

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Disclosure forms provided by the authors are available at NEJM.org.

Author Affiliations: From the Office of the Director (D.M.M.) and the Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases (J.K.T.), National Institute of Allergy and Infectious Diseases, Bethesda, MD.

Keywords: Pandemic Influenza; Spanish Flu; H1N1; History.

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#Spanishflu in #Italy: new #data, new questions (Infez Med., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Infez Med. 2018 Mar 1;26(1):97-106.

Spanish flu in Italy: new data, new questions.

Fornasin A1, Breschi M2, Manfredini M3.

Author information: 1 Department of Economics and Statistics, University of Udine, Italy. 2 Department of Economics and Business, University of Sassari, Italy. 3 Department of Life Sciences, University of Parma, Italy.

 

Abstract

This paper proposes a new estimate for the number of victims of Spanish flu in Italy and highlights some aspects of mortality closely linked to the First World War. The sources used are official death statistics and the Albo d’oro, a roll of honor of the Italians fallen in the First World War. The new estimate of deaths from the flu is 410,000 for 1918, which should be raised to 466,000 when the numbers are taken up to 1920. Deaths from Spanish flu among the military were about 70,000. The time sequence of deaths recognizes two distinct peaks, one in October and one in November 1918. Between these two peaks, the lowest number of deaths falls in the week of the armistice between Italy and Austria-Hungary (signed 4 November 1918). This suggests links between Spanish flu and WWI that cannot be merely explained in terms of movement of people and contagion.

PMID: 29525806[Indexed for MEDLINE] Free full text

Keywords: Pandemic Influenza; Spanish Flu; H1N1; Italy; Society; Wars.

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#Natality #Decline and Spatial #Variation in Excess #Death Rates During the 1918-1920 #Influenza #Pandemic in #Arizona, #USA (Am J Epidemiol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Am J Epidemiol. 2018 Dec 1;187(12):2577-2584. doi: 10.1093/aje/kwy146.

Natality Decline and Spatial Variation in Excess Death Rates During the 1918-1920 Influenza Pandemic in Arizona, United States.

Dahal S1, Mizumoto K1,2, Bolin B3, Viboud C, Chowell G1,4.

Author information: 1 Department of Population Health Sciences, School of Public Health, Georgia State University, Atlanta, Georgia. 2 Graduate School of Medicine, Hokkaido University, Hokkaido, Japan. 3 School of Human Evolution and Social Change, Arizona State University, Tempe, Arizona. 4 Division of International Epidemiology and Population Studies, Fogarty International Center, National Institutes of Health, Bethesda, Maryland.

 

Abstract

A large body of epidemiologic research has concentrated on the 1918 influenza pandemic, but more work is needed to understand spatial variation in pandemic mortality and its effects on natality. We collected and analyzed 35,151 death records from Arizona for 1915-1921 and 21,334 birth records from Maricopa county for 1915-1925. We estimated the number of excess deaths and births before, during, and after the pandemic period, and we found a significant decline in the number of births occurring 9-11 months after peak pandemic mortality. Moreover, excess mortality rates were highest in northern Arizona counties, where Native Americans were historically concentrated, suggesting a link between ethnic and/or sociodemographic factors and risk of pandemic-related death. The relationship between birth patterns and pandemic mortality risk should be further studied at different spatial scales and in different ethnic groups.

PMID: 30508194 DOI: 10.1093/aje/kwy146

Keywords: Pandemic Influenza; H1N1; Spanish Flu; Society; USA; Arizona.

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