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.

PROMED comment

Date: Sun 10 Oct 2004
From: Mark Hughes <mthughes@colostate.edu>


The inhibitor sensitivity of constructs containing 1918 HA, NA or M genes
-----------------------------------------------
The HA, NA, and M gene products from the 1918 strain of influenza A
(H1N1) virus have been tested for sensitivity to oseltamivir,
zanamivir, and amantadine/rimantidine. The reference is: Tumpey TM,
Garcia-Sastre A, Mikulasova A, Taubenberger JK, Swayne DE, Palese P,
Basler CF. Existing antivirals are effective against influenza
viruses with genes from the 1918 pandemic virus. Proc Natl Acad Sci
USA. 2002 Oct 15;99(21):13849-54.

--
Mark Hughes, Ph.D.
Arthropod-Borne and Infectious Disease Laboratory
Colorado State University,
Fort Collins, CO
<mthughes@colostate.edu>

[ProMED-mail is indebted to Mark Hughes for drawing attention to this
paper. In the paper, the authors report similar experiments to those
of Kawaoka and colleagues and state that: "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, the authors 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 anti-influenza 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." - Mod.CP]