Existing antivirals are effective against influenza viruses with genes from the 1918 pandemic virus - PubMed (original) (raw)

Existing antivirals are effective against influenza viruses with genes from the 1918 pandemic virus

Terrence M Tumpey et al. Proc Natl Acad Sci U S A. 2002.

Abstract

The 1918 influenza pandemic caused more than 20 million deaths worldwide. Thus, the potential impact of a re-emergent 1918 or 1918-like influenza virus, whether through natural means or as a result of bioterrorism, is of significant concern. The genetic determinants of the virulence of the 1918 virus have not been defined yet, nor have specific clinical prophylaxis and/or treatment interventions that would be effective against a re-emergent 1918 or 1918-like virus been identified. Based on the reported nucleotide sequences, we have reconstructed the hemagglutinin (HA), neuraminidase (NA), and matrix (M) genes of the 1918 virus. Under biosafety level 3 (agricultural) conditions, we have generated recombinant influenza viruses bearing the 1918 HA, NA, or M segments. Strikingly, recombinant viruses possessing both the 1918 HA and 1918 NA were virulent in mice. In contrast, a control virus with the HA and NA from a more recent human isolate was unable to kill mice at any dose tested. The recombinant viruses were also tested for their sensitivity to U.S. Food and Drug Administration-approved antiinfluenza virus drugs in vitro and in vivo. Recombinant viruses possessing the 1918 NA or both the 1918 HA and 1918 NA were inhibited effectively in both tissue culture and mice by the NA inhibitors, zanamivir and oseltamivir. A recombinant virus possessing the 1918 M segment was inhibited effectively both in tissue culture and in vivo by the M2 ion-channel inhibitors amantadine and rimantadine. These data suggest that current antiviral strategies would be effective in curbing the dangers of a re-emergent 1918 or 1918-like virus.

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Figures

Figure 1

Figure 1

Inhibition in vitro of the 1918 influenza virus NA by zanamivir and GS4071 (oseltamivir carboxylate). Extracts expressing WSN NA, New Caledonia NA, or 1918 NA were assayed in the presence of the indicated concentrations of zanamivir (a) or GS4071 (oseltamivir carboxylate) (b). Activities are given as percent activity relative to the no-drug control.

Figure 2

Figure 2

Oseltamivir effectively inhibits replication in tissue culture of recombinant influenza viruses possessing the 1918 NA and prevents lethal infection in mice of the recombinant 1918 HA/1918 NA influenza virus. (a) Inhibition of plaque formation by GS4071 (oseltamivir carboxylate). Plaque-reduction assays were performed on MDCK cells by using the indicated concentrations of drug following established methods (29). (b) Oral administration of oseltamivir protects mice from death due to intranasal infection with the 1918 HA/1918 NA virus. Indicated is the percentage of mice surviving intranasal infection at the indicated times postinfection.

Figure 3

Figure 3

Inhibition of virus plaque formation by amantadine and rimantadine. (a) Percent inhibition of plaque formation in the presence of the indicated concentrations of amantadine hydrochloride. (b) Percent inhibition of plaque formation in the presence of the indicated concentrations of rimantadine hydrochloride. Recombinant, wild-type (WT) WSN virus (circles), Udorn M virus (triangles), and 1918 M virus (squares) were tested for their ability to form plaques in the presence of the indicated concentrations of drug. The data are reported as the percent inhibition of plaque formation as compared with a no-drug control for each virus.

Figure 4

Figure 4

Rimantadine protects mice from lethal infection with an influenza virus possessing the 1918 M segment. (a) Survival after infection with the indicated viruses and either mock treatment with PBS or treatment with rimantadine. An uninfected but treated control group was included also. (b) Average weight of mice from the same groups as in a. Average weight is reported for all mice surviving at the indicated time points. Groups of 8 or 9 mice were infected with 10 LD50 of wild-type (WT) WSN virus (circles) or 1918 M virus (squares) or with 106 pfu of Udorn M virus (1 LD80, triangles). The mice then were mock-treated with PBS (filled symbols) or treated with 40 mg/kg of body weight of rimantadine hydrochloride (open symbols). PBS or drug was administered i.p. beginning 6 h postinfection and once daily afterward. One group of mice was left uninfected and treated with rimantadine (filled diamonds).

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