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. 2009 Jun;83(11):5864-8.
doi: 10.1128/JVI.02649-08. Epub 2009 Mar 18.

Acquisition of a polybasic hemagglutinin cleavage site by a low-pathogenic avian influenza virus is not sufficient for immediate transformation into a highly pathogenic strain

Olga Stech  1 , Jutta Veits, Siegfried Weber, Daniela Deckers, Diana Schröer, Thomas W Vahlenkamp, Angele Breithaupt, Jens Teifke, Thomas C Mettenleiter, Jürgen Stech
Affiliations

Acquisition of a polybasic hemagglutinin cleavage site by a low-pathogenic avian influenza virus is not sufficient for immediate transformation into a highly pathogenic strain

Olga Stech et al. J Virol. 2009 Jun.

Abstract

Highly pathogenic avian influenza viruses (HPAIV) differ from all other strains by a polybasic cleavage site in their hemagglutinin. All these HPAIV share the H5 or H7 subtype. In order to investigate whether the acquisition of a polybasic cleavage site by an avirulent avian influenza virus strain with a hemagglutinin other than H5 or H7 is sufficient for immediate transformation into an HPAIV, we adapted the hemagglutinin cleavage site of A/Duck/Ukraine/1/1963 (H3N8) to that of the HPAIV A/Chicken/Italy/8/98 (H5N2), A/Chicken/HongKong/220/97 (H5N1), or A/Chicken/Germany/R28/03 (H7N7) and generated the recombinant wild-type and cleavage site mutants. In contrast to the wild type, multicycle replication of these mutants in tissue culture was demonstrated by positive plaque assays and viral multiplication in the absence of exogenous trypsin. Therefore, in vitro all cleavage site mutants resemble an HPAIV. However, in chicken they did not exhibit high pathogenicity, although they could be reisolated from cloacal swabs to some extent, indicating enhanced replication in vivo. These results demonstrate that beyond the polybasic hemagglutinin cleavage site, the virulence of HPAIV in chicken is based on additional pathogenicity determinants within the hemagglutinin itself or in the other viral proteins. Taken together, these observations support the notion that acquisition of a polybasic hemagglutinin cleavage site by an avirulent strain with a non-H5/H7 subtype is only one among several alterations necessary for evolution into an HPAIV.

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Figures

FIG. 1.
FIG. 1.
In vitro replication of DkUkr63-Wt in comparison with the HACS mutants DkUkr63-It98HACS, DkUkr63-Hk220HACS, and DkUkr63-R28HACS. (A) Plaque assays on MDCK cells in the presence and in the absence of trypsin. (B) Western blots of supernatants from infected MDCK cells incubated in the presence (T) and in the absence (−) of trypsin, using a monoclonal antibody specific to an HA of the H3 serotype.
FIG. 2.
FIG. 2.
Multicycle growth curves of DkUkr63-Wt (blue), DkUkr63-It98HACS (red), DkUkr63-Hk220HACS (orange), and DkUkr63-R28HACS (brown) on MDCK and QT6 cells in the presence (diamonds) and in the absence (circles) of trypsin.
FIG. 3.
FIG. 3.
Virulence in chickens. Survival and disease after oculonasal inoculation with PBS (mock), DkUkr63-Wt, DkUkr63-It98HACS, DkUkr63-Hk220HACS, or DkUkr63-R28HACS. The birds were observed for 10 days for clinical signs and classified as healthy (0), slightly ill (0.5), or ill (1); the daily clinical index (DCI) was calculated from the sum of individual clinical scores from all birds divided by the number of animals per group (10 chickens). Chickens 3 and 9 from the group infected with DkUkr63-It98HACS developed central nervous symptoms.
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