Avian Influenza (H5N1) Viruses Isolated from Humans in Asia in 2004 Exhibit Increased Virulence in Mammals

Maines, Taronna R.; Lu, Xui Hua; Erb, Steven M.; Edwards, Lindsay E.; Guarner, Jeannette; Greer, Patricia W.; Nguyen, Doan C.; Szretter, Kristy J.; Chen, Limei; Thawatsupha, Pranee; Chittaganpitch, Malinee; Waicharoen, Sunthareeya; Nguyen, Diep Thi Ngoc; Nguyen, Tung; Nguyen, Hanh Thi Ngoc; Kim, Jae Hong; Hoang, Long T.; Kang, Chun; Phuong, Lien S.; Lim, Wilina; Zaki, Sherif R.; Donis, Ruben O.; Cox, Nancy J.; Katz, Jacqueline M.; Tumpey, Terrence M.

doi:10.1128/jvi.79.18.11788-11800.2005

Cited by 426 publications

(476 citation statements)

References 42 publications

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“…The human H3N2 influenza A viruses Vic75 and Pan99 and the avian H5N1 influenza A viruses HK486, HK213, Indo05, and VN30408 were used in this study. Virus stocks were prepared in 10-day-old eggs as described (29) except that human viruses were incubated at 33.5°C for 48 h, whereas reassortant viruses were incubated at 37°C for 48 h. All research with H5N1 viruses or reassortant viruses was conducted under biosafety level 3 containment, including enhancements required by the U.S. Department of Agriculture and the Select Agent Program (see interim guidance at www.cdc.gov͞flu͞h2n2bsl3.htm).…”

Section: Methodsmentioning

confidence: 99%

“…Reassortant viruses were rescued as described (33) by using the 12-plasmid Vic75 system, the eight-plasmid HK486 system, or a combination of the two. The genetic makeup of each reassortant virus was confirmed by sequencing as described (29 were inoculated, and nasal washes were collected and analyzed as described (29). FID 50 titers were determined by inoculating groups of nine ferrets i.n.…”

Section: Methodsmentioning

confidence: 99%

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Lack of transmission of H5N1 avian–human reassortant influenza viruses in a ferret model

Maines

Chen

Matsuoka

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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316

360

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Avian influenza A H5N1 viruses continue to spread globally among birds, resulting in occasional transmission of virus from infected poultry to humans. Probable human-to-human transmission has been documented rarely, but H5N1 viruses have not yet acquired the ability to transmit efficiently among humans, an essential property of a pandemic virus. The pandemics of 1957 and 1968 were caused by avian-human reassortant influenza viruses that had acquired human virus-like receptor binding properties. However, the relative contribution of human internal protein genes or other molecular changes to the efficient transmission of influenza viruses among humans remains poorly understood. Here, we report on a comparative ferret model that parallels the efficient transmission of H3N2 human viruses and the poor transmission of H5N1 avian viruses in humans. In this model, an H3N2 reassortant virus with avian virus internal protein genes exhibited efficient replication but inefficient transmission, whereas H5N1 reassortant viruses with four or six human virus internal protein genes exhibited reduced replication and no transmission. These findings indicate that the human virus H3N2 surface protein genes alone did not confer efficient transmissibility and that acquisition of human virus internal protein genes alone was insufficient for this 1997 H5N1 virus to develop pandemic capabilities, even after serial passages in a mammalian host. These results highlight the complexity of the genetic basis of influenza virus transmissibility and suggest that H5N1 viruses may require further adaptation to acquire this essential pandemic trait. transmissibility ͉ pandemic virus properties ͉ pandemic influenza ͉ animal model ͉ receptor specificity

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Lack of transmission of H5N1 avian–human reassortant influenza viruses in a ferret model

Maines

Chen

Matsuoka

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

316

360

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“…Next, inhibition of the polymerase complex of a highly pathogenic H5N1 influenza virus (isolated from a fatal human case in Vietnam 27 ) was assessed in a mini-replicon reporter assay 28 . As previously shown, wt MxA inhibited viral replication by 80% (Fig.…”

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confidence: 99%

Structural basis of oligomerization in the stalk region of dynamin-like MxA

Gao

Malsburg

Paeschke

et al. 2010

Nature

226

428

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GTPase is a key mediator of cell-autonomous innate immunityHis-tagged full-length human MxA (Fig. 1a) was recombinantly expressed in bacteria and purified to homogeneity (Methods, Supp. Fig. 1). In crystallization trials, small needle-shaped protein crystals were obtained which represented proteolytic cleavage products of the MD and GED (Supp. Fig. 2). We solved the phase problem by a single anomalous dispersion protocol and could build and refine a model containing two molecules in the asymmetric unit (Methods, Supp. Table 1 and 2). Each monomer spans nearly the complete MD and the amino(N-)-terminal part of the GED (amino acids 366-633) which together fold into an elongated anti-parallel fourhelical bundle where the MD contributes three helices and the GED one (Fig. 1b, Supp. Fig. 3). This segment corresponds to the stalk region of dynamin 7 , and we refer to it as stalk of MxA. The first visible amino acid, Glu366, is 15 amino acids downstream of the last visible residue of the corresponding G-domain structure in rat dynamin (Supp. Fig. 3) 8 . It marks the start of helix α1 in the MxA stalk which is divided in α1 N and α1 C by a 10 amino acid long loop, L1, introducing a 30° kink. A putative loop L2 (amino acids 438-447) opposite of the deduced position of the G-domain is not visible in our structure. L2 was previously demonstrated to be the target of a functionally neutralising monoclonal antibody 9,10 . Helix α2 runs anti-parallel to α1 back to the G-domain. It ends in a short loop L3 and is followed by helix α3 that extends in parallel to α1. The 40 amino acid long loop L4 (residues 532-572) is at the equivalent sequence position as the PH domain of dynamin (Fig. 1a, Supp. Fig. 3) and is absent in our model. L4 is predicted to be unstructured and was previously shown to be proteinase K sensitive 11 .At the C-terminus, the GED supplies 44 residues to helix α4 which proceeds in parallel to helix α2 back to the G-domain. It is followed by a short helix α5 which directs the polypeptide chain towards the N-terminus of the MD. The carboxy(C-)-terminal 30 highly conserved residues of the GED known to be involved in antiviral specificity 12 are missing in our model. In dynamin, the corresponding residues were shown to directly interact with the G-domain 13 . The stalk of MxA is divergent from the corresponding structures of other dynamin superfamily members, such as GBP1 14 , EHD2 15 and BDLP 16 although some features are shared (Supp. Fig. 4). 4 In the crystal lattice, each MxA stalk is assembled in a criss-cross pattern resulting in a linear oligomer, where each stalk contributes three distinct interfaces (Fig. 1c). Such an arrangement of the stalks is plausible for the Mx oligomer since all G-domains would be located at one side of the oligomer whereas the putative substrate-binding site in L2 and L4 would be located at the opposite side (Fig. 1b, c).The hydrophobic interface-1 covering 1300 Å 2 is conserved among Mx proteins and dynamins and has a two-fold symmetry between the associating monomers (Fig....

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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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Avian Influenza (H5N1) Viruses Isolated from Humans in Asia in 2004 Exhibit Increased Virulence in Mammals

Cited by 426 publications

References 42 publications

Lack of transmission of H5N1 avian–human reassortant influenza viruses in a ferret model

Lack of transmission of H5N1 avian–human reassortant influenza viruses in a ferret model

Structural basis of oligomerization in the stalk region of dynamin-like MxA

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

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