Viral Genetics

Introduction The terms mutant, strain, type, variant and even isolate have all been used extensively and rather loosely without discrimination. All of these terms were used to designate a virus that differs in some inheritable way from a parental or wild virus. It is now recognized that what is designated wild type may not accurately reflect the nature of a virus or a gene as it is isolated from nature (field isolate).

Wild Type It is an arbitrary designation that has a narrow connotation, used to designate the original, usually laboratory- adapted strain of a virus from which mutants are selected and to which those mutants are compared. Strain It is often used to designate different wild types of the same virus (isolated from different geographical locations or patients).

Type It has come to be synonymous with serotype as determined by neutralization of infectivity. Variant It is generally used to indicate a virus that is phenotypically different from the wild type but for which the genotypic basis of the variation is unknown.

Genetically, Viruses have many features in common with cells: Viruses are subject to mutations. The genomes of different viruses can recombine to form novel progeny. The expression of the viral genome can be regulated. Viral gene products can interact.

Regarding genetic variation in viruses, two principal mechanisms are involved:- Mutation Recombination Such variation may lead to the emergence of new viral serotypes or viruses of altered virulence.

Spontaneous Mutation Spontaneous mutations accumulate in the genomes of viruses and induce the variation in phenotype that is subjected to selection pressure during the evolution of a virus. The rates of spontaneous mutation can be as low as 10-8 to 10-11 per incorporated nucleotides in DNA genomes. In viruses with RNA genomes, higher rates of spontaneous mutations have been measured, in the order of 10-3 to 10-4 per incorporated nucleotides

While the genomes of DNA viruses are relatively stable, the high rates of spontaneous mutation in RNA genomes suggest that the concept of wild type is very fleeting in RNA genome systems. However, wild type RNA viruses replicate more rapidly than mutants dominating population, but other factors operate to favor the accumulation of mutants in a virus population (difficulty in production of genetically homogenous high- titer virus stocks).

Types of Mutation Null mutation Temperature- Sensitive Mutation Cold-sensitive mutation Plaque- morphology Mutation Host-Range Mutations

Types of Mutation…cont’d Antibody Escape / Resistance Mutation Revertants, Suppressors, and Heterozygosis Lethal Mutations Deletion mutations Attenuated Mutations

Mutations in essential genes inactivate the virus, but mutations in other genes can produce antiviral drug resistance or alter the antigenicity or pathogencity of the virus. Not all mutations that occur persist in the virus population. Mutations that interfere with the essential functions of attachment, penetration, uncoating, replication, assembly and release do not permit multiplication and are rapidly lost from the population.

However, because of the redundancy of the genetic code, many mutations are neutral, resulting either in no change in the viral protein or in replacement of an amino acid by a functionally similar amino acid. Only mutations that do not cripple essential viral functions can persist or become fixed in a virus population.

Virus-Virus Interactions Virus–Virus and Virus–Host interactions that Affect Phenotype and genotype Virus-Virus Interactions A- Phenotypically Pyenotypic Mixing:- - Capsid derived from both viruses - Transcapsidation and pseudotype formation Interference Autointerference Homologous interference Heterologous interference

Complementation Mechanisms of interference : 1- Blocking of receptor ( inhibition of adsorption). 2- Competition for components of the replicative apparatus (sites and/ or substrates). 3- Inhibitors of replication (interferon). Significance in natural infections, polyvalent vaccination and vaccine and infection. Complementation

B- Genotypic Interactions 1- Recombination 2- Genetic Reactivation a- Marker rescue b- Multiplicity Reactivation Mechanisms Independent reassortment (multipartite RNA viruses) Incompletely linked genes ( DNA, RNA viruses). - break –rejoin mechanism (DNA viruses) - copy- choice mechanism (RNA viruses)

Recombination by independent assortment during dual infection

Recombination by break-rejoin of incompletely linked genes

Recombination by copy-choice of incompletely linked genes