Unraveling the genetic basis of virulence has long been one of the major goals of animal virology, and also one of the most difficult to achieve, since many genes, both viral and host, are involved in the outcome of each infection. With advances in molecular genetics it has been possible to dissect the problem in a more precise way, using techniques such as recombinant DNA technology, genetic reassortment, site-specific mutagenesis, and transgenic animals
Ol necessity, most experimental work has been carried out with laboratory animals. The most detailed studies have been those conducted with retroviruses and oncogenic DNA viruses to determine the genetic basis of cellular transformation and oncogenicity (see Chapter 11). Experiments with herpesviruses are beginning to reveal the genetic basis of latency with these viruses (see Chapter 10). With viruses causing acute infections, those with segmented genomes have provided a more easily manipulated experimental model, since each segment of the genome of influenza viruses and reoviruses, lor example, is in most cases equivalent to one gene, and reassortants can be readily obtained. Study of a number of réassortants involving difterent genome segments enables the functions that relate to virulence to be assigned to particular genes. Using a different approach, a detailed understanding of the basis of virulence at the molecular level has been obtained with polioviruses, where it has been possible to compare the sequences of the genomes of wild-type viruses with those of avirulent vaccine strains and then with virulent revertants that arise from time to time in vaccinees or their contacts Investigations with vaccinia virus have revealed the complexity of the armamentarium of gene products directed against various components of innate or acquired host resistance. Some examples are outlined below to illustrate how molecular biology has opened up the new field of molecular pathogenesis
Most viral genes encode proteins that are essential for viral replication, notably those required for viral entry into the principal host cells, replication of the viral genome, and assembly/release of new virions (see Table 3-3) Additional genes have evolved to maximize the yield of virions by down-regulating expression of cellular genes and up-regulating expression of particular viral genes (and sometimes ol particular cellular genes) at appropriate stages of the replication cycle Recently we have come to recognize a third category of viral genes, which are irrelevant to intracellular replication of virus per se, but which optimize the spread and the ultimate tiler of virus in the body as a whole, principally by suppressing various arms of the immune response These gene products are called vnaktncs
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