Last data update: Apr 22, 2024. (Total: 46599 publications since 2009)
Records 1-17 (of 17 Records) |
Query Trace: Chesnokov A [original query] |
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Influenza C virus susceptibility to antivirals with different mechanisms of action
Chesnokov A , Ivashchenko AA , Matsuzaki Y , Takashita E , Mishin VP , Ivachtchenko AV , Gubareva LV . Antimicrob Agents Chemother 2024 e0172723 Antiviral susceptibility of influenza viruses was assessed using a high-content imaging-based neutralization test. Cap-dependent endonuclease inhibitors, baloxavir and AV5116, were superior to AV5115 against type A viruses, and AV5116 was most effective against PA mutants tested. However, these three inhibitors displayed comparable activity (EC(50) 8-22 nM) against type C viruses from six lineages. Banana lectin and a monoclonal antibody, YA3, targeting the hemagglutinin-esterase protein effectively neutralized some, but not all, type C viruses. |
New insights into the neuraminidase-mediated hemagglutination activity of influenza A(H3N2) viruses
Gao R , Pascua PNQ , Nguyen HT , Chesnokov A , Champion C , Mishin VP , Wentworth DE , Gubareva LV . Antiviral Res 2023 218 105719 Influenza virus neuraminidase (NA) can act as a receptor-binding protein, a role commonly attributed to hemagglutinin (HA). In influenza A(H3N2) viruses, three NA amino acid residues have previously been associated with NA-mediated hemagglutination: T148, D151, and more recently, H150. These residues are part of the 150-loop of the NA monomer. Substitutions at 148 and 151 arise from virus propagation in laboratory cell cultures, whereas changes at 150 occurred during virus evolution in the human host. In this study, we examined the effect of natural amino acid polymorphism at position 150 on NA-mediated hemagglutination. Using the A/Puerto Rico/8/34 backbone, we generated a comprehensive panel of recombinant A(H3N2) viruses that have different NAs but shared an HA that displays poor binding to red blood cells (RBCs). None of the tested substitutions at 150 (C, H, L, R, and S) promoted NA-binding. However, we identified two new determinants of NA-binding, Q136K and T439R, that emerged during virus culturing. Similar to T148I, both Q136K and T439R reduced NA enzyme activity by 48-86% and inhibition (14- to 173-fold) by the NA inhibitor zanamivir. NA-binding was observed when a virus preparation contained approximately 10% of NA variants with either T148I or T439R, highlighting the benefit of using deep sequencing in virus characterization. Taken together, our findings provide new insights into the molecular mechanisms underlying the ability of NA to function as a binding protein. Information gained may aid in the design of new and improved NA-targeting antivirals. |
Antiviral susceptibility of clade 2.3.4.4b highly pathogenic avian influenza A(H5N1) viruses isolated from birds and mammals in the United States, 2022
Nguyen HT , Chesnokov A , De La Cruz J , Pascua PNQ , Mishin VP , Jang Y , Jones J , Di H , Ivashchenko AA , Killian ML , Torchetti MK , Lantz K , Wentworth DE , Davis CT , Ivachtchenko AV , Gubareva LV . Antiviral Res 2023 217 105679 Clade 2.3.4.4 b highly pathogenic avian influenza (HPAI) A (H5N1) viruses that are responsible for devastating outbreaks in birds and mammals pose a potential threat to public health. Here, we evaluated their susceptibility to influenza antivirals. Of 1015 sequences of HPAI A (H5N1) viruses collected in the United States during 2022, eight viruses (∼0.8%) had a molecular marker of drug resistance to an FDA-approved antiviral: three adamantane-resistant (M2-V27A), four oseltamivir-resistant (NA-H275Y), and one baloxavir-resistant (PA-I38T). Additionally, 31 viruses contained mutations that may reduce susceptibility to inhibitors of neuraminidase (NA) (n = 20) or cap-dependent endonuclease (CEN) (n = 11). A panel of 22 representative viruses was tested phenotypically. Overall, clade 2.3.4.4 b A (H5N1) viruses lacking recognized resistance mutations were susceptible to FDA-approved antivirals. Oseltamivir was least potent at inhibiting NA activity, while the investigational NA inhibitor AV5080 was most potent, including against NA mutants. A novel NA substitution T438N conferred 12-fold reduced inhibition by zanamivir, and in combination with the known marker N295S, synergistically affected susceptibility to all five NA inhibitors. In cell culture-based assays HINT and IRINA, the PA-I38T virus displayed 75- to 108-fold and 37- to 78-fold reduced susceptibility to CEN inhibitors baloxavir and investigational AV5116, respectively. Viruses with PA-I38M or PA-A37T showed 5- to 10-fold reduced susceptibilities. As HPAI A (H5N1) viruses continue to circulate and evolve, close monitoring of drug susceptibility is needed for risk assessment and to inform decisions regarding antiviral stockpiling. |
An optimized cell-based assay to assess influenza virus replication by measuring neuraminidase activity and its applications for virological surveillance
Patel MC , Flanigan D , Feng C , Chesnokov A , Nguyen HT , Elal AA , Steel J , Kondor RJ , Wentworth DE , Gubareva LV , Mishin VP . Antiviral Res 2022 208 105457 Year-round virological characterization of circulating epidemic influenza viruses is conducted worldwide to detect the emergence of viruses that may escape pre-existing immunity or acquire resistance to antivirals. High throughput phenotypic assays are needed to complement the sequence-based analysis of circulating viruses and improve pandemic preparedness. The recent entry of a polymerase inhibitor, baloxavir, into the global market further highlighted this need. Here, we optimized a cell-based assay that considerably streamlines antiviral and antigenic testing by replacing lengthy immunostaining and imaging procedures used in current assay with measuring the enzymatic activity of nascent neuraminidase (NA) molecules expressed on the surface of virus-infected cells. For convenience, this new assay was named IRINA (Influenza Replication Inhibition Neuraminidase-based Assay). IRINA was successfully validated to assess inhibitory activity of baloxavir on virus replication by testing a large set (>150) of influenza A and B viruses, including drug resistant strains and viruses collected during 2017-2022. To test its versatility, IRINA was utilized to evaluate neutralization activity of a broadly reactive human anti-HA monoclonal antibody, FI6, and post-infection ferret antisera, as well as the inhibition of NA enzyme activity by NA inhibitors. Performance of IRINA was tested in parallel using respective conventional assays. IRINA offers an attractive alternative to current phenotypic assays, while maintaining reproducibility and high throughput capacity. Additionally, the improved turnaround time may prove to be advantageous when conducting time sensitive studies, such as investigating a new virus outbreak. This assay can meet the needs of surveillance laboratories by providing a streamlined and cost-effective approach for virus characterization. |
Cluster of Oseltamivir-Resistant and Hemagglutinin Antigenically Drifted Influenza A(H1N1)pdm09 Viruses, Texas, USA, January 2020
Mohan T , Nguyen HT , Kniss K , Mishin VP , Merced-Morales AA , Laplante J , St George K , Blevins P , Chesnokov A , De La Cruz JA , Kondor R , Wentworth DE , Gubareva LV . Emerg Infect Dis 2021 27 (7) 1953-1957 Four cases of oseltamivir-resistant influenza A(H1N1)pdm09 virus infection were detected among inhabitants of a border detention center in Texas, USA. Hemagglutinin of these viruses belongs to 6B.1A5A-156K subclade, which may enable viral escape from preexisting immunity. Our finding highlights the necessity to monitor both drug resistance and antigenic drift of circulating viruses. |
Susceptibility of widely diverse influenza a viruses to PB2 polymerase inhibitor pimodivir.
Patel MC , Chesnokov A , Jones J , Mishin VP , De La Cruz JA , Nguyen HT , Zanders N , Wentworth DE , Davis TC , Gubareva LV . Antiviral Res 2021 188 105035 Pimodivir exerts an antiviral effect on the early stages of influenza A virus replication by inhibiting the cap-binding function of polymerase basic protein 2 (PB2). In this study, we used a combination of sequence analysis and phenotypic methods to evaluate pimodivir susceptibility of influenza A viruses collected from humans and other hosts. Screening PB2 sequences for substitutions previously associated with reduced pimodivir susceptibility revealed a very low frequency among seasonal viruses circulating in the U.S. during 2015-2020 (<0.01%; 3/11,934) and among non-seasonal viruses collected in various countries during the same period (0.2%; 18/8971). Pimodivir potently inhibited virus replication in two assays, a single-cycle HINT and a multi-cycle FRA, with IC(50) values in a nanomolar range. Median IC(50) values determined by HINT were similar for both subtypes of seasonal viruses, A (H1N1)pdm09 and A (H3N2), across three seasons. Human seasonal viruses with PB2 substitutions S324C, S324R, or N510K displayed a 27-317-fold reduced pimodivir susceptibility. In addition, pimodivir was effective at inhibiting replication of a diverse group of animal-origin viruses that have pandemic potential, including avian viruses of A (H5N6) and A (H7N9) subtypes. A rare PB2 substitution H357N was identified in an A (H4N2) subtype poultry virus that displayed >100-fold reduced pimodivir susceptibility. Our findings demonstrate a broad inhibitory activity of pimodivir and expand the existing knowledge of amino acid substitutions that can reduce susceptibility to this investigational antiviral. |
Detection of baloxavir resistant influenza A viruses using next generation sequencing and pyrosequencing methods.
Patel MC , Mishin VP , De La Cruz JA , Chesnokov A , Nguyen HT , Wilson MM , Barnes J , Kondor RJG , Wentworth DE , Gubareva LV . Antiviral Res 2020 182 104906 Baloxavir, a new antiviral drug targeting cap-dependent endonuclease activity of polymerase acidic (PA) protein of influenza viruses, is now approved in multiple countries. Several substitutions at isoleucine 38 in PA protein (e.g., PA-I38T) have been associated with decreased baloxavir susceptibility in vitro and in vivo. In recent years, next generation sequencing (NGS) analysis and pyrosequencing have been used by CDC and U.S. Public Health Laboratories to monitor drug susceptibility of influenza viruses. Here we described an improved pyrosequencing assay for detecting influenza A viruses carrying substitutions at PA-38. Cyclic and customized orders of nucleotide dispensation were evaluated, and pyrosequencing results were compared to those generated using NGS. Our data showed that the customized nucleotide dispensation has improved the pyrosequencing assay performance in identification of double mixtures (e.g., PA-38I/T); however, identification of PA-38 variants in triple mixtures remains a challenge. While NGS analysis indicated the presence of PA-I38K in one clinical specimen and isolate, our attempts to detect this mutation by pyrosequencing or recover the virus carrying PA-I38K in cell culture were unsuccessful, raising a possibility of a rarely occurring sequencing error. Overall, pyrosequencing provides a convenient means to detect baloxavir resistant influenza viruses when NGS is unavailable or a faster turnaround time is required. |
Anti-PfGARP activates programmed cell death of parasites and reduces severe malaria.
Raj DK , Das Mohapatra A , Jnawali A , Zuromski J , Jha A , Cham-Kpu G , Sherman B , Rudlaff RM , Nixon CE , Hilton N , Oleinikov AV , Chesnokov O , Merritt J , Pond-Tor S , Burns L , Jolly G , Ben Mamoun C , Kabyemela E , Muehlenbachs A , Lambert L , Orr-Gonzalez S , Gnadig NF , Fidock DA , Park S , Dvorin JD , Pardi N , Weissman D , Mui BL , Tam YK , Friedman JF , Fried M , Duffy PE , Kurtis JD . Nature 2020 582 (7810) 104-108 Malaria caused by Plasmodium falciparum remains the leading single-agent cause of mortality in children1, yet the promise of an effective vaccine has not been fulfilled. Here, using our previously described differential screening method to analyse the proteome of blood-stage P. falciparum parasites2, we identify P. falciparum glutamic-acid-rich protein (PfGARP) as a parasite antigen that is recognized by antibodies in the plasma of children who are relatively resistant—but not those who are susceptible—to malaria caused by P. falciparum. PfGARP is a parasite antigen of 80 kDa that is expressed on the exofacial surface of erythrocytes infected by early-to-late-trophozoite-stage parasites. We demonstrate that antibodies against PfGARP kill trophozoite-infected erythrocytes in culture by inducing programmed cell death in the parasites, and that vaccinating non-human primates with PfGARP partially protects against a challenge with P. falciparum. Furthermore, our longitudinal cohort studies showed that, compared to individuals who had naturally occurring anti-PfGARP antibodies, Tanzanian children without anti-PfGARP antibodies had a 2.5-fold-higher risk of severe malaria and Kenyan adolescents and adults without these antibodies had a twofold-higher parasite density. By killing trophozoite-infected erythrocytes, PfGARP could synergize with other vaccines that target parasite invasion of hepatocytes or the invasion of and egress from erythrocytes. |
Susceptibility of influenza A, B, C, and D viruses to Baloxavir
Mishin VP , Patel MC , Chesnokov A , De La Cruz J , Nguyen HT , Lollis L , Hodges E , Jang Y , Barnes J , Uyeki T , Davis CT , Wentworth DE , Gubareva LV . Emerg Infect Dis 2019 25 (10) 1969-1972 Baloxavir showed broad-spectrum in vitro replication inhibition of 4 types of influenza viruses (90% effective concentration range 1.2-98.3 nmol/L); susceptibility pattern was influenza A > B > C > D. This drug also inhibited influenza A viruses of avian and swine origin, including viruses that have pandemic potential and those resistant to neuraminidase inhibitors. |
Replicative fitness of seasonal influenza A viruses with decreased susceptibility to baloxavir
Chesnokov A , Patel MC , Mishin VP , De La Cruz JA , Lollis L , Nguyen HT , Dugan V , Wentworth DE , Gubareva LV . J Infect Dis 2019 221 (3) 367-371 Susceptibility of influenza A viruses to baloxavir can be affected by changes at amino acid residue 38 in polymerase acidic (PA) protein. Information on replicative fitness of PA-I38-substituted viruses remains sparse. We demonstrated that substitutions I38L/M/S/T not only had a differential effect on baloxavir susceptibility (9- to 116-fold), but also on in vitro replicative fitness. While I38L conferred undiminished growth, other substitutions led to mild attenuation. In a ferret model, control viruses outcompeted those carrying I38M or I38T substitutions, although their advantage was limited. These findings offer insights into the attributes of baloxavir resistant viruses needed for informed risk assessment. |
Insights into the antigenic advancement of influenza A(H3N2) viruses, 2011-2018.
Jorquera PA , Mishin VP , Chesnokov A , Nguyen HT , Mann B , Garten R , Barnes J , Hodges E , De La Cruz J , Xu X , Katz J , Wentworth DE , Gubareva LV . Sci Rep 2019 9 (1) 2676 Influenza A(H3N2) viruses evade human immunity primarily by acquiring antigenic changes in the haemagglutinin (HA). HA receptor-binding features of contemporary A(H3N2) viruses hinder traditional antigenic characterization using haemagglutination inhibition and promote selection of HA mutants. Thus, alternative approaches are needed to reliably assess antigenic relatedness between circulating viruses and vaccines. We developed a high content imaging-based neutralization test (HINT) to reduce antigenic mischaracterization resulting from virus adaptation to cell culture. Ferret reference antisera were raised using clinical specimens containing viruses representing recent vaccine strains. Analysis of viruses circulating during 2011-2018 showed that gain of an N158-linked glycosylation in HA was a molecular determinant of antigenic distancing between A/Hong Kong/4801/2014-like (clade 3C.2a) and A/Texas/50/2012-like viruses (clade 3C.1), while multiple evolutionary HA F193S substitution were linked to antigenic distancing from A/Switzerland/97152963/2013-like (clade 3C.3a) and further antigenic distancing from A/Texas/50/2012-like viruses. Additionally, a few viruses carrying HA T135K and/or I192T showed reduced neutralization by A/Hong Kong/4801/2014-like antiserum. Notably, this technique elucidated the antigenic characteristics of clinical specimens, enabling direct characterization of viruses produced in vivo, and eliminating in vitro culture, which rapidly alters the genotype/phenotype. HINT is a valuable new antigenic analysis tool for vaccine strain selection. |
Assessing baloxavir susceptibility of influenza viruses circulating in the United States during the 2016/17 and 2017/18 seasons
Gubareva LV , Mishin VP , Patel MC , Chesnokov A , Nguyen HT , De La Cruz J , Spencer S , Campbell AP , Sinner M , Reid H , Garten R , Katz JM , Fry AM , Barnes J , Wentworth DE . Euro Surveill 2019 24 (3) The anti-influenza therapeutic baloxavir targets cap-dependent endonuclease activity of polymerase acidic (PA) protein. We monitored baloxavir susceptibility in the United States with next generation sequencing analysis supplemented by phenotypic one-cycle infection assay. Analysis of PA sequences of 6,891 influenza A and B viruses collected during 2016/17 and 2017/18 seasons showed amino acid substitutions: I38L (two A(H1N1)pdm09 viruses), E23G (two A(H1N1)pdm09 viruses) and I38M (one A(H3N2) virus); conferring 4-10-fold reduced susceptibility to baloxavir. |
A Pyrosequencing-Based Approach to High-Throughput Identification of Influenza A(H3N2) Virus Clades Harboring Antigenic Drift Variants.
Mishin VP , Baranovich T , Garten R , Chesnokov A , Abd Elal AI , Adamczyk M , LaPlante J , George KS , Fry AM , Barnes J , Chester SC , Xu X , Katz JM , Wentworth DE , Gubareva LV . J Clin Microbiol 2016 55 (1) 145-154 Rapid evolution of influenza A(H3N2) viruses necessitates close monitoring of their antigenic properties so emergence and spread of antigenic drift variants can be rapidly identified. Changes in hemagglutinin (HA) acquired by contemporary A(H3N2) viruses hinder antigenic characterization by traditional methods, thus complicating vaccine strain selection. Sequence-based approaches have been used to infer virus antigenicity; however, they are time-consuming and mid-throughput. To facilitate virological surveillance and epidemiological studies, we have developed and validated a pyrosequencing approach that enables identification of six HA clades of contemporary A(H3N2) viruses. The identification scheme of H3 clade 3C.2, 3C.2a, 3C.2b, 3C.3, 3C.3a and 3C.3b viruses is based on the interrogation of five SNPs within three neighboring HA regions: 412-431; 465-481; and 559-571. Two bioinformatics tools, IdentiFire (Qiagen) and FireComb (developed in-house) were utilized to expedite pyrosequencing data analysis. The assay's analytical sensitivity was 10 focus forming units; and respiratory specimens with CT value < 34 typically produced good quality pyrograms. When applied to 120 A(H3N2) virus isolates and 27 respiratory specimens, the assay displayed 100% agreement with clades determined by HA sequencing coupled with phylogenetics. The multi-SNP analysis described here was readily adopted by another laboratory with pyrosequencing capabilities. Implementation of this approach enhanced virological surveillance and epidemiological studies from 2013-2016 when over 3000 A(H3N2) viruses were examined. |
Enhanced genetic characterization of influenza A(H3N2) viruses and vaccine effectiveness by genetic group, 2014-2015.
Flannery B , Zimmerman RK , Gubareva LV , Garten RJ , Chung JR , Nowalk MP , Jackson ML , Jackson LA , Monto AS , Ohmit SE , Belongia EA , McLean HQ , Gaglani M , Piedra PA , Mishin VP , Chesnokov AP , Spencer S , Thaker SN , Barnes JR , Foust A , Sessions W , Xu X , Katz J , Fry AM . J Infect Dis 2016 214 (7) 1010-9 BACKGROUND: During the 2014-15 US influenza season, expanded genetic characterization of circulating influenza A(H3N2) viruses was used to assess the impact of genetic variability of influenza A(H3N2) viruses on influenza vaccine effectiveness (VE). METHODS: A novel pyrosequencing assay was used to determine genetic group based on hemagglutinin (HA) gene sequences of influenza A(H3N2) viruses from patients enrolled US Flu Vaccine Effectiveness network sites. Vaccine effectiveness was estimated using a test-negative design comparing vaccination among patients infected with influenza A(H3N2) viruses and uninfected patients. RESULTS: Among 9710 enrollees, 1868 (19%) tested positive for influenza A(H3N2); genetic characterization of 1397 viruses showed 1134 (81%) belonged to one HA genetic group (3C.2a) of antigenically drifted H3N2 viruses. Effectiveness of 2014-15 influenza vaccination varied by A(H3N2) genetic group from 1% (95% confidence interval [CI], -14% to 14%) against illness caused by antigenically drifted A(H3N2) group 3C.2a viruses versus 44% (95% CI, 16% to 63%) against illness caused by vaccine-like A(H3N2) group 3C.3b viruses. CONCLUSION: Effectiveness of 2014-15 influenza vaccination varied by genetic group of influenza A(H3N2) virus. Changes in hemagglutinin genes related to antigenic drift were associated with reduced vaccine effectiveness. |
Neuraminidase mutations conferring resistance to oseltamivir in influenza A(H7N9) viruses
Marjuki H , Mishin VP , Chesnokov AP , De La Cruz JA , Davis CT , Villanueva JM , Fry AM , Gubareva LV . J Virol 2015 89 (10) 5419-26 Human infections by avian influenza A(H7N9) virus entail substantial morbidity and mortality. Treatment of infected patients with the neuraminidase (NA) inhibitor oseltamivir was associated with emergence of viruses carrying NA substitutions. In the NA inhibition (NI) assay, R292K conferred highly reduced inhibition by oseltamivir, while E119V and I222K each caused reduced inhibition. To facilitate establishment of laboratory correlates of clinically relevant resistance, experiments were conducted in ferrets infected with virus carrying wild-type or variant NA genes recovered from the A/Taiwan/1/2013 isolate. Oseltamivir treatment (5 or 25 mg/kg/dose) was given 4 hours post-infection followed by twice daily treatment for 5 days. Treatment of ferrets infected with wild-type virus resulted in a modest dose-dependent reduction (0.7-1.5 log10TCID50) in nasal wash viral titers and inflammation response. Conversely, treatment failed to significantly inhibit the replication of R292K or E119V viruses. A small reduction of viral titers was detected on day 5 in ferrets infected with the I222K virus. Propensity for oseltamivir resistance emergence was assessed in oseltamivir-treated animals infected with wild-type virus; emergence of R292K virus was detected in 3 of 6 ferrets within 5-7 days post-infection. Collectively, we demonstrate that R292K, E119V and I222K reduced the inhibitory activity of oseltamivir not only in the NI assay, but also in infected ferrets, judged particularly by viral loads in nasal washes, and may signal the need for alternative therapeutics. Thus, these clinical outcomes measured in the ferret model may correlate with clinically relevant oseltamivir resistance in humans. IMPORTANCE: This report provides more evidence for using the ferret model to assess susceptibility of influenza A(H7N9) viruses to oseltamivir, the most prescribed anti-influenza drug. The information gained can be used to assist in the establishment of laboratory correlates of human disease and drug therapy. The rapid emergence of viruses with R292K in treated ferrets correlates well with the multiple reports on this NA variant in treated human patients. Our findings highlight the importance for discovery and characterization of new antiviral drugs with different mechanism of action and the use of combination treatment strategies against emerging viruses with pandemic potential such as avian H7N9 virus, particularly against those carrying drug resistance markers. |
Characterization of drug-resistant influenza A(H7N9) variant viruses isolated from an oseltamivir-treated patient in Taiwan
Marjuki H , Mishin VP , Chesnokov AP , Jones J , De La Cruz JA , Sleeman K , Tamura D , Nguyen HT , Wu HS , Chang FY , Liu MT , Fry AM , Cox NJ , Villanueva JM , Davis CT , Gubareva LV . J Infect Dis 2014 211 (2) 249-57 BACKGROUND: Patients contracting influenza A(H7N9) often developed severe disease causing respiratory failure. Neuraminidase (NA) inhibitors (NAIs) are the primary option for treatment, but information on drug-resistance markers for A(H7N9) is limited. METHODS: Four NA variants of A/Taiwan/1/2013 (H7N9) virus containing a single substitution (NA-E119 V, NA-I222 K, NA-I222R or NA-R292 K), recovered from an oseltamivir-treated patient, were tested for NAI susceptibility in vitro; their replicative fitness was evaluated in cell culture, mice and ferrets. RESULTS: NA-R292 K led to highly reduced inhibition by oseltamivir and peramivir, while NA-E119 V, NA-I222 K and NA-I222R caused reduced inhibition by oseltamivir. Mice infected with any virus showed severe clinical signs with high mortality rates. NA-I222 K virus was the most virulent in mice, whereas virus lacking NA change (NA-WT) and NA-R292 K virus seemed the least virulent. Sequence analysis suggests that PB2-S714N increased virulence of the NA-I222 K virus in mice; NS1-K126R, alone or in combination with PB2-V227M, produced contrasting effects in NA-WT and NA-R292 K viruses. In ferrets, all viruses replicated to high titers in the upper respiratory tract, but produced only mild illness. NA-R292 K virus, showed reduced replicative fitness in this animal model. CONCLUSIONS: Our data highlight challenges in assessment of replicative fitness of H7N9 NA variants emerged in NAI-treated patients. |
An investigational antiviral drug, DAS181, effectively inhibits replication of zoonotic influenza A virus subtype H7N9 and protects mice from lethality
Marjuki H , Mishin VP , Chesnokov AP , De La Cruz JA , Fry AM , Villanueva J , Gubareva LV . J Infect Dis 2014 210 (3) 435-40 Human infections caused by the avian influenza A(H7N9) virus have been associated with substantial morbidity and mortality. Emergence of virus variants, carrying markers of decreased susceptibility to neuraminidase inhibitors, was reported. Here we showed that fludase, an antiviral drug with sialidase activity, potently inhibited replication of wild-type H7N9 viruses and their oseltamivir-resistant R292 K variants in mice. A once-daily administration initiated early after lethal infection, hampered body weight loss and completely protected mice from lethality. We observed a time-dependent effect for 24-72-hour delayed fludase treatments on morbidity and mortality. The results warrant further investigation of fludase for influenza treatment. |
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