Efficacy of Oseltamivir Therapy in Ferrets Inoculated with Different Clades of H5N1 Influenza Virus

Govorkova, Elena A.; Ilyushina, Natalia A.; Boltz, David A.; Douglas, A. R.; Yılmaz, Neziha; Webster, Robert G.

doi:10.1128/aac.01312-06

Cited by 141 publications

(125 citation statements)

References 52 publications

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Section: Discussionmentioning

confidence: 99%

“…Previous studies showed that inoculation of ferrets with as few as 10 EID 50 s of A/Vietnam/1203/04 (H5N1) virus caused systemic spread and death, whereas 10 6 EID 50 s of A/Turkey/15/06 (H5N1) virus were not lethal (13). A/Vietnam/1203/04 is a unique H5N1 virus that rapidly triggers multiple events in infected hosts and is characterized by broad tissue tropism, highly efficient replication, and rapid immune system dysregulation (13,42). Virus-host interactions in an A/Vietnam/1203/04 (H5N1) virus-ferret model were affected by high virus virulence, and studies with A/Turkey/15/06 (H5N1) virus were undertaken to obtain experimental evidence on the fitness of oseltamivir-resistant variants versus sensitive variants in the background of a less virulent virus that possesses lower efficiency of replication (13).…”

Section: Discussionmentioning

confidence: 99%

“…A/Vietnam/1203/04 is a unique H5N1 virus that rapidly triggers multiple events in infected hosts and is characterized by broad tissue tropism, highly efficient replication, and rapid immune system dysregulation (13,42). Virus-host interactions in an A/Vietnam/1203/04 (H5N1) virus-ferret model were affected by high virus virulence, and studies with A/Turkey/15/06 (H5N1) virus were undertaken to obtain experimental evidence on the fitness of oseltamivir-resistant variants versus sensitive variants in the background of a less virulent virus that possesses lower efficiency of replication (13). The less virulent A/Hanoi/30408/05 (H5N1) influenza virus carrying the H274Y NA mutation was reported to yield reduced titers in ferret nasal washes (30).…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Competitive Fitness of Oseltamivir-Sensitive and -Resistant Highly Pathogenic H5N1 Influenza Viruses in a Ferret Model

Govorkova

Ilyushina

Marathe

et al. 2010

J Virol

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The fitness of oseltamivir-resistant highly pathogenic H5N1 influenza viruses has important clinical implications. We generated recombinant human A/Vietnam/1203/04 (VN; clade 1) and A/Turkey/15/06 (TK; clade 2.2) influenza viruses containing the H274Y neuraminidase (NA) mutation, which confers resistance to NA inhibitors, and compared the fitness levels of the wild-type (WT) and resistant virus pairs in ferrets. The VN-H274Y and VN-WT viruses replicated to similar titers in the upper respiratory tract (URT) and caused comparable disease signs, and none of the animals survived. On days 1 to 3 postinoculation, disease signs caused by oseltamivir-resistant TK-H274Y virus were milder than those caused by TK-WT virus, and all animals survived. We then studied fitness by using a novel approach. We coinoculated ferrets with different ratios of oseltamivir-resistant and -sensitive H5N1 viruses and measured the proportion of clones in day-6 nasal washes that contained the H274Y NA mutation. Although the proportion of VN-H274Y clones increased consistently, that of TK-H274Y virus decreased. Mutations within NA catalytic (R292K) and framework (E119A/K, I222L, H274L, and N294S) sites or near the NA enzyme active site (V116I, I117T/V, Q136H, K150N, and A250T) emerged spontaneously (without drug pressure) in both pairs of viruses. The NA substitutions I254V and E276A could exert a compensatory effect on the fitness of VN-H274Y and TK-H274Y viruses. NA enzymatic function was reduced in both drug-resistant H5N1 viruses. These results show that the H274Y NA mutation affects the fitness of two H5N1 influenza viruses differently. Our novel method of assessing viral fitness accounts for both virus-host interactions and virus-virus interactions within the host.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Competitive Fitness of Oseltamivir-Sensitive and -Resistant Highly Pathogenic H5N1 Influenza Viruses in a Ferret Model

Govorkova

Ilyushina

Marathe

et al. 2010

J Virol

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“…Currently, ferrets are used for influenza drug testing; for example, neuraminidase inhibitors are effective during ferret influenza infection [38][39][40]. Importantly, ferrets display immunological memory and cross-protective immunity, the cornerstones of vaccine mechanism, and are therefore ideal for the use of testing the safety and efficacy of human vaccines [41][42][43][44][45].…”

mentioning

confidence: 99%

The current state of H5N1 vaccines and the use of the ferret model for influenza therapeutic and prophylactic development

Banner

Kelvin²

2012

J Infect Dev Ctries

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Highly pathogenic avian influenza H5N1 is a threat to global public health as a natural pandemic causing agent but has recently been considered a bioterrorism concern. The evolving view of the H5N1 virus necessitates the re-evaluation of the current status of H5N1 therapeutics and prophylactics, in particular the preparation of viable H5N1 vaccination strategies as well as the use of ferrets in influenza research. Here the highly pathogenic H5N1 virus dilemma is discussed in context with the current H5N1 vaccine status and the use of the ferret model. Previously, the development of various H5N1 vaccine platforms have been attempted, many of them tested in the ferret model, including vector vaccines, adjuvant vaccines, DNA vaccines, and reverse engineered vaccines. Moreover, as ferrets are a superlative animal model for influenza investigation and vaccine testing, it is imperative that this model is recognized for its uses in prophylactic development and not only as an agent for creating transmissible influenza viruses. Elucidating the ferret immune response and creating ferret immune reagents remain important goals in conjunction with the development and manufacture of H5N1 vaccines. In summary, an efficacious H5N1 vaccine is urgently needed and the ferret model remains an appropriate model for its development.J Infect Dev Ctries 2012; 6(6):465-469.

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“…In animal models of lethal influenza virus infection, H5N1 virus has been isolated from multiple organs, including lungs, brain, liver, spleen, and kidney (Maines et al, 2005;Yen et al, 2005;Govorkova et al, 2007). In our study, mice receiving 1-day regimens survived while viral replication in the lungs was inhibited; however, the subsequent increase of lung titers to equal those in control untreated mice was associated with death.…”

Section: Discussionmentioning

confidence: 50%

Intramuscularly administered neuraminidase inhibitor peramivir is effective against lethal H5N1 influenza virus in mice

Boltz¹,

Ilyushina²,

Arnold³

et al. 2008

Antiviral Research

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The replication efficiency and multi-organ dissemination of some influenza A (H5N1) viruses requires a rapid (re)evaluation of the available antiviral strategies. We assessed five regimens of the neuraminidase (NA) inhibitor peramivir in mice inoculated with H5N1 virus. The regimens differed by: (1) frequency of administration on first day (once vs twice); (2) duration of administration (1 day vs 8 days); (3) route of administration (intramuscular [IM] injection alone or followed by oral administration). In all regimens, BALB/c mice were administered 30 mg/kg peramivir IM one hour after lethal challenge with 5 MLD 50 of A/Vietnam/1203/04 (H5N1) influenza virus. When given only on the day of inoculation, a single IM injection produced a 33% survival rate, which increased to 55% with two injections. Eight-day regimens significantly increased survival; two IM injections followed by 7 daily IM injections was the most effective regimen (100% survival; inhibition of replication in lungs and brain). When this 8-day regimen began at 24 hours after inoculation, 78% of mice survived; 56% survived when treatment began at 48 after hours. Anti-HA antibody titer differed with the peramivir regimen and corresponded to the severity of disease. Overall, our results demonstrate that IM administration of peramivir is effective in promoting the survival of mice infected with systemically replicating H5N1 virus.

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Efficacy of Oseltamivir Therapy in Ferrets Inoculated with Different Clades of H5N1 Influenza Virus

Cited by 141 publications

References 52 publications

Competitive Fitness of Oseltamivir-Sensitive and -Resistant Highly Pathogenic H5N1 Influenza Viruses in a Ferret Model

Competitive Fitness of Oseltamivir-Sensitive and -Resistant Highly Pathogenic H5N1 Influenza Viruses in a Ferret Model

The current state of H5N1 vaccines and the use of the ferret model for influenza therapeutic and prophylactic development

Intramuscularly administered neuraminidase inhibitor peramivir is effective against lethal H5N1 influenza virus in mice

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