Generation Of Viral Diversity

Although the classification system facilitates virus identification, the constant emergence of new, diverse viral populations continues to challenge scientists. Three major mechanisms give rise to viral diversity: mutation, reassortment, and recombination. Depending upon the replication strategy of a particular virus, the relative contribution of these pathways differs. Nucleotide misin-corporation leading to mutation occurs for all viruses but is dramatically different for viruses with RNA versus DNA intermediates. Errors are made both by DNA and RNA polymerases, but while DNA polymerases have proofreading capacity, RNA polymerases do not. Consequently, errors generated by RNA polymerases are incorporated into the newly generated viral genome at a very high rate. The error rates of DNA polymerases can be as low as one base substitution per every 108-1011 nucleotides, whereas the RNA polymerases have error rates as high as one base substitution per every 103-106 nucleotides.4 In the case of RNA viruses, virus population studies of patient and tissue culture isolates have shown the coexistence of numerous viral genomes with slightly different sequences, or quasi-species.

Homologous or nonhomologous recombination is another mechanism by which new viruses are generated and has played a significant role in virus evolution. Large DNA viruses can not only recombine with each other but also contain genes usurped from the host. RNA tumor viruses have incorporated cellular oncogenes that lead to transformation in some cell types. For RNA viruses, recombination probably occurs via incomplete synthesis and template RNA switching during negative-strand synthesis. This process occurs with high frequency in poliovirus infection, with an estimated 10%-20% of poliovirus genomic RNA recombining in a single growth cycle.5 In polio eradication efforts, a live virus preparation consisting of three separate attenuated poliovirus strains was used. Despite the safety of each attenuated strain, some vaccinated patients did develop poliomyelitis. Through genetic testing of patient isolates, it became clear that the recovered virus was not the same as the administered vaccine, and that neurovirulence had been restored by recombination among the three attenuated strains.6-7

Reassortment can also occur when two related viruses with segmented genomes infect a single cell. For example, reassortment is responsible for gen erating new influenza A strains that are antigenically different enough from previous strains to infect and cause disease. Besides the annual flu season, severe pandemics have occurred such as the Spanish flu of 1918, the Asian flu of 1957, the Hong Kong flu of 1968, and the Russian flu of 1977.8 Influenza virus infects several animal hosts, including humans, pigs, horses, and its natural reservoir, waterfowl. The two major antigenic proteins of this virus, hemagglutinin (HA) and neuraminidase (NP), can be reassorted between different influenza viruses, generating new strains different from the two parental strains (called antigenic shift). Each influenza strain is given a code which identifies its HA and NP proteins. The Spanish flu was caused by the H1N1 strain, the Asian flu was strain H2N2, the Hong Kong flu was strain H3N2, and the Russian flu was strain H1N1.9

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