Hiv

p!5E

Protein kinase C

Inhibits signal transduction

that is, (hat in general, and for influenza virus m particular, no one gene determines virulence. Recent studies show that one essential requirement for virulence in the chicken and neurovirulence in the mouse is that the hemagglutinin protein (HA) must be cleaved. In nonpathogenic strains of avian influenza virus, the HA1 and HA2 polypeptide chains of the hemagglutinin are linked by a single arginine, whereas in virulent strains the linker is a sequence of several basic amino acids and is more readily cleaved by the available cellular protease(s). Virulent strains thus contain HA which is activated (cleaved) in a wide spectrum of different types of cells; hence, they can replicate and spread throughout the host. Nonpathogenic strains, on the other hand, soon reach a barrier of cells which lack appropriate HA-cleaving enzymes.

Perhaps the most striking demonstration of how a minor single nucleotide change in the HA gene can make all the difference between relative avirulence and high virulence was the finding that a single amino acid substitution in the HA protein of influenza A, subtype H5, in )983 led to a devastating outbreak of fowl plague on poultry larms around Pennsylvania that caused losses amounting to over $60,000,000. The point mutation abolished a glycosylation site, thus exposing to proteolysis the cleavage site previously concealed by an oligosaccharide side chain. However, virulence is only partly explained by this factor, for when reassortants were made between highly virulent and avirulent strains of avian influenza virus, exchange of any one of the eight RNA segments modified the virulence. Studies with a variety of réassortants showed that, for each reassortant, an optimal combination of genes (the optimal "gene constellation") was selected which favored survival in nature and determined virulence.

Reovirus

Detailed analyses of the virulence of reoviruses for mice have been carried out with reassortant viruses The fact that the protein product of each of the ten genome segments has been isolated and characlerized has allowed determination of their functions and effects on virulence (Table 7-2).

Four genes (SI, M2, L2, and S4) encode the four polypeptides that are found on the outer capsid (Fig. 7-1). Each plays a role in determining viru-

Table 7-2

Genetic Analysis ni Virulence of Reoviruses, Based on Studies with Mutants and Reassortants

Table 7-2

Genetic Analysis ni Virulence of Reoviruses, Based on Studies with Mutants and Reassortants

Gene l'rolein

Properties

Significance in infections of mice

SI rrl

Reovirus 3 binds to neurons

Neural spread, encephalitis

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