The viruses are obligate intracellular pathogens. They replicate only in a living host cell. Viruses, like other living beings, obey the law of genetics. The viruses show variation in their genomic structure by two principal methods—mutations and recombination.
Mutation is the most important mechanism of genetic modification in viruses. Mutations occur spontaneously and readily in viral genomes causing frequent changes in the nucleic acids. This results in production of new viral strains showing properties different from parental or wild-type virus. Mutations occur during every viral infection; the frequency of mutations being about 1024 to 1015. New variants of strains are identified by their nucleotide sequence, antigenic differences, or by differences in their structural or functional properties. Mutations in the essential genes of virus cause inactivation of the virus. This is known as lethal mutation. However, mutations in the other genes alter antigenicity and pathogenicity of the virus and induce drug resistance in viruses. Mutations in viruses may be induced by mutagens, e.g., irradiation or chemical agents, such as 5-fluorouracil, or even may occur spontaneously.
Mutations in essential genes are known as lethal mutations. Mutations in viruses lead to formation of various mutants, which show new functional or structural proteins. This leads to formation of new viral mutants, which are difficult to iso-late because the virus cannot replicate. Selective removal or loss of a portion of the viral genome and subsequent loss of func-tion that it encodes leads to the formation of deletion mutant. Other mutations may produce:
Attenuated emutants—variant strains that cause less seri-ous infections in humans and animals.
Host range mutants—variant strains showing differencesin the tissue type and species of target cells affected by viruses.
Plaque mutants—variant strains showing difference intheir size or their appearance in infected host cells.
Conditional mutants—e.g., temperature-sensitive or cold-sensitive mutants.
Genetic recombination may occur when two different but related viruses infect a cell simultaneously. This leads to extramolecular genetic exchange between two viruses, leading to production of a progeny virion that possesses genes from both the viruses. Genetic recombination may occur between (a) two active infectious viruses, (b) one active and another inactive virus, and (c) two inactive viruses. Following types of genetic recombination may occur when a host cell is affected by two viruses:
1. Intramolecular recombination
Intramolecular recombination occurs between two closely related DNA viruses. For example, infection of the host cell by two closely related herpesviruses, such as herpes simplex virus type 1 and 2 produces recombinant, new hybrid strains. These new hybrid strains possess genes from both viruses: type 1 and 2. This process has also been observed in closely related RNA viruses. For example, recombination of Sindbis and eastern equine encephalitis virus has led to the formation of western equine encephalitis virus, another togavirus.
Reassortment is another process of genetic recombination. It occurs between viruses with segmented genomes, such as influenza virus A and B (8 segments), Reoviridae (10–12 segments), Bunyaviridae (3 segments), and Arenaviridae and Birnaviridae (2 segments). An exchange of segments occurs between these viruses, resulting in production of new hybrid strains. Synthesis of new strains of influenza A by coinfection with a virus from different species is an example of genetic recombination by reassortment that occurs in nature.
It is of two types: (a) cross-reactivation or marker rescue and (b) multiplicity reactivation.
Cross-reactivation (marker rescue): This occurs betweenan active virus and a related inactive virus, resulting in a progeny possessing one or more genetic traits of the inactivated virus. For example, in influenza virus, when a new epidemic strain (e.g., strain A1) that does not often grow well in eggs as compared to the established strain is grown in eggs along with a standard strain (e.g., strain A2) inactivated by UV irradiation, it results in production of a new hybrid strain. The hybrid strain may have antigenic properties of strain A2 but genetic characteristics of A1. Such viruses have been evaluated widely in production of influenza vaccines. Marker rescue is also used to map the genome of herpes simplex virus.
Multiplicity reactivation: This is a phenomenon in whichlive virus may be produced when a cell is infected with two or more (high multiplicity) virus particles of the same virus, each of which has suffered lethal mutation in a different gene due to UV irradiation. Thus from the total genetic pool, it may be possible to obtain a full complement of undamaged genes, resulting in production of infectious virion progeny. Therefore, there is a potential danger of multiplicity reactivation occurring following the administration of UV-irradiated vaccine. So UV irradiation is not a safe method of producing inactivated virus vaccine.
Nongenetic interaction between viral gene products takes place in following four ways: (a) complementation, (b) phenotypic mixing, (c) genotype mixing, and (d) interference.
Complementation is a functional interaction between the gene products of two viruses, when two viruses (one or both of which may be infective) infect a cell simultaneously. In this process, their gene products, such as proteins and enzymes, comple-ment action of each other so as to have increased yield of one or both viruses. This occurs even between unrelated viruses. In this process, a defective virus strain can be rescued by the replication of another mutant or by a wild-type strain. For example, adenovirus is defective in simian cell but it can be rescued by SV40. The SV40 virus can grow in monkey cells and produce a gene product that adenovirus needs, thereby comple-menting replication of adenovirus.
In this process, virus products from cells infected with different virus strains may be phenotypically mixed and have the proper-ties of one strain but the genome of other. This is not a stable variation; on subsequent passage, the capsid will be found to be of the original type only. In phenotypic mixing, when the nucleic acid of one virus is surrounded by the entire capsid of the other virus, it is called transcapsidation. Pseudotypes are produced when transcapsidation occurs between different types of viruses, but this is rare.
All the viruses of vertebrates are haploid except retroviruses which are diploid; but sometimes several nucleocapsids may be enclosed within a single envelope. This phenomenon of genotypic mixing is known as polyploidy. No recombination between the genomes of the virus takes place, and it is not a stable change.
Interference denotes inhibition of growth of one virus in a host cell when it is simultaneously infected with another virus. Interferon is the most important mediator of interfer-ence. Autointerference is another type of interference, in which a high multiplicity of infection inhibits production of infectious progeny. In contrast, mixed infections sometimes increase the yield of one virus and produce well-marked cytopathic effects in the cell lines. This phenomenon is called enhancement.