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The fact is evident, that in case of the pandemic development the highly productive virus infection in the cells of upper respiratory tract must happen. It is accompanied by accumulation of large quantity of a new virus, which can be actively passed from human to human by respiratory route. The transformation of avian influenza virus (AIV) to pandemic virus can occur in four stages. First, the avian virus has to "learn" how to infect efficiently epithelial cells of human nasopharynx and trachea. For this purpose, the mutation changes of HA1 and HA2, fulfilling the attaching and 'undressing' functions during adsorption and penetration of the virus into cells of human upper respiratory tract, in hemagglutinin (HA) of AIV have to take place. Also it is necessary to strengthen the affinity of HA of AIV, contributing to the specific adsorption, by introducing the carbohydrate component of the host cells (human, pig or other mammals).
Then, AIV has to obtain the ability for high level accumulation of their components in the nasopharynx and trachea cells. It can be achieved by way of the formation of reassortant, consisted of the core of human influenza virus and envelope of AIV or of the first adaptation (the mutation changes in the genes of transcriptase complex) of AIV, which, most likely, can take place in the organism of the intermediate host (pig).
The full infectious particles capable to infect the cells of upper respiratory tract of other people have to be formed. The mutation changes in the HA AIV structure is a mechanism of their formation. As a result the large molecule of HA will obtain the property to be cleaved effectively into two subunits (HA1, HA2). It is important that the mutation changes in the site of HA1 attachment and in the site of HA2 fusion already exist on this stage of the virus reproduction.
Finally, the fixation of dangerous mutants of reassortant or adapted virus in human population (by means of natural selection) and the formation of genetically stable pathogen with new properties (possibly pandemic virus) has to take place.
Analysis of mechanisms of changes of AIV properties in the line of pandemic virus shows that this process is a step-wise depending on randomized combinations of many factors. The highly pathogenic AIV A (H5N1) in its pandemic potency has not been changed during the last years from the moment of its first isolation in 1997. As previously people are getting ill with influenza extremely rarely, human-to-human transmission was not observed. Only one among four basic stages of AIV properties changes, necessary for its conversion into pandemic virus, is partially realized. As a result of natural selection of spontaneous mutants the hemagglutinin of avian virus has obtained genetically heritable property to be cleaved by different proteases, including trypsin-like proteases of human upper respiratory tract epithelium. The high pathogenicity of AIV (H5N1) for human isn't obligatory for accelerated appearance of the globally dangerous virus, based on determination of the main conditions of the pandemic appearance. Virus has to be pathogenic enough to generate the acute disease. In contrast, the low pathogenic AIV in nature has more possibilities for changing its properties than highly pathogenic one. The danger of fast appearance of avian virus with pandemic potency is evidently overestimated. And the world doesn't stand before a global pandemic. Long-time 'period of pandemic danger' is therefore 'interpandemic period'. Nevertheless, taking into account the 'avian' origin of the late pandemic viruses (H1N1, H2N2, H3N2), the pandemic in future, are more than likely. Etiology of pandemic can be predictable only after appearance the first epidemic episode of influenza with proven spreading of the new virus from human to human.