<i>In Vitro</i>Antiviral Activity of Favipiravir (T-705) against Drug-Resistant Influenza and 2009 A(H1N1) Viruses

Sleeman, Katrina; Mishin, Vasiliy P.; Deyde, Varough; Furuta, Yoshihiko; Klimov, Alexander; Gubareva, Larisa V.

doi:10.1128/aac.01739-09

Cited by 135 publications

(113 citation statements)

References 47 publications

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“…Notably, T-705 yielded comparable values for both oseltamivir-susceptible and oseltamivir-resistant viruses, suggesting that T-705 is effective against both. These data support previous reports of T-705 antiviral activity against oseltamivir-resistant and amantadine-resistant influenza viruses (6,14). In addition, no specific amino acid substitutions in the polymerase gene were detected, and no viable viruses were detected after several serial passages.…”

Section: Discussionsupporting

confidence: 79%

“…The agent showed potent activity in vitro against flaviviruses (8), bunyaviruses (9), arenaviruses (9, 10), noroviruses (11), seasonal influenza A (H1N1, H2N2, and H3N2), B, and C viruses (6), and influenza A (H5N1) viruses (12,13). Importantly, viruses resistant to both oseltamivir and amantadine were susceptible to T-705 (6,14). Orally administered T-705 at a dose of Ն30 mg/kg of body weight/day prevented death, inhibited lung consolidation, and reduced lung virus titers in BALB/c mice lethally challenged with H5N1-and H3N2-subtype viruses (12,13).…”

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confidence: 99%

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T-705 (Favipiravir) Induces Lethal Mutagenesis in Influenza A H1N1 Viruses In Vitro

Baranovich

Wong

Armstrong

et al. 2013

J Virol

358

352

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Several novel anti-influenza compounds are in various phases of clinical development. One of these, T-705 (favipiravir), has a mechanism of action that is not fully understood but is suggested to target influenza virus RNA-dependent RNA polymerase. We investigated the mechanism of T-705 activity against influenza A (H1N1) viruses by applying selective drug pressure over multiple sequential passages in MDCK cells. We found that T-705 treatment did not select specific mutations in potential target proteins, including PB1, PB2, PA, and NP. Phenotypic assays based on cell viability confirmed that no T-705-resistant variants were selected. In the presence of T-705, titers of infectious virus decreased significantly (P < 0.0001) during serial passage in MDCK cells inoculated with seasonal influenza A (H1N1) viruses at a low multiplicity of infection (MOI; 0.0001 PFU/cell) or with 2009 pandemic H1N1 viruses at a high MOI (10 PFU/cell). There was no corresponding decrease in the number of viral RNA copies; therefore, specific virus infectivity (the ratio of infectious virus yield to viral RNA copy number) was reduced. Sequence analysis showed enrichment of G¡A and C¡T transversion mutations, increased mutation frequency, and a shift of the nucleotide profiles of individual NP gene clones under drug selection pressure. Our results demonstrate that T-705 induces a high rate of mutation that generates a nonviable viral phenotype and that lethal mutagenesis is a key antiviral mechanism of T-705. Our findings also explain the broad spectrum of activity of T-705 against viruses of multiple families.

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Section: Discussionsupporting

confidence: 79%

mentioning

confidence: 99%

T-705 (Favipiravir) Induces Lethal Mutagenesis in Influenza A H1N1 Viruses In Vitro

Baranovich

Wong

Armstrong

et al. 2013

J Virol

358

352

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“…Samples were subtyped based the CDC real-time RT-PCR Diagnostic assay and/or HI assay (35). Infectious virus titers were determined using focus formation assays and MDCK-SIAT1 cells (36). The resulted virus titers were expressed as the number of focus forming units (FFU) per milliliter.…”

Section: Methodsmentioning

confidence: 99%

A Pyrosequencing-Based Approach to High-Throughput Identification of Influenza A(H3N2) Virus Clades Harboring Antigenic Drift Variants

et al. 2017

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The rapid evolution of influenza A(H3N2) viruses necessitates close monitoring of their antigenic properties so the 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 midthroughput. To facilitate virological surveillance and epidemiological studies, we developed and validated a pyrosequencing approach that enables identification of six HA clades of contemporary A(H3N2) viruses. The identification scheme of viruses of the H3 clades 3C.2, 3C.2a, 3C.2b, 3C.3, 3C.3a, and 3C.3b is based on the interrogation of five single nucleotide polymorphisms (SNPs) within three neighboring HA regions, namely 412 to 431, 465 to 481, and 559 to 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 threshold cycle (C T ) values of Ͻ34 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. The implementation of this approach enhanced the findings from virological surveillance and epidemiological studies between 2013 and 2016, which examined more than 3,000 A(H3N2) viruses.KEYWORDS A(H3N2), genotyping, influenza, pyrosequencing S ince their introduction into the human population in 1968, influenza A(H3N2) viruses have been responsible for seasonal epidemics and associated with both a prolonged duration of the epidemic season and a greater disease severity (1-4). The hemagglutinin (HA) glycoprotein is the major surface antigen of influenza viruses; it is also responsible for the receptor binding and membrane fusion required for entrance into susceptible host cells (5). Decades ago, this glycoprotein was named "hemagglutinin" for its ability to bind and bridge erythrocytes. The other surface antigen, neuraminidase (NA), is a receptor-destroying enzyme (6). As with other seasonal influenza viruses, A(H3N2) viruses undergo genetic and antigenic changes, called antigenic drift,

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“…(Fig. 2H) which has demonstrated a potent and selective inhibitory activity against a range of different influenza strains both in vitro and in vivo (18), including H5N1 and oseltamivir resistant H1N1 2009 strain (76). In timing-of-addition studies, it has been established that T-705 targets the early-to middle-stages of the viral replication cycle and that the compound neither has an effect on viral adsorption, nor on viral release (19).…”

Section: Nucleoside Analogues Ribavirin (Copegusmentioning

confidence: 99%

Chemotherapy of Influenza: Current and Novel Approach

Simeonova

Galabov

2011

Biotechnology & Biotechnological Equipment

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In VitroAntiviral Activity of Favipiravir (T-705) against Drug-Resistant Influenza and 2009 A(H1N1) Viruses

Cited by 135 publications

References 47 publications

T-705 (Favipiravir) Induces Lethal Mutagenesis in Influenza A H1N1 Viruses In Vitro

T-705 (Favipiravir) Induces Lethal Mutagenesis in Influenza A H1N1 Viruses In Vitro

A Pyrosequencing-Based Approach to High-Throughput Identification of Influenza A(H3N2) Virus Clades Harboring Antigenic Drift Variants

Chemotherapy of Influenza: Current and Novel Approach

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