Genetics of virus 

Just as in higher life forms, viral genetic material is subject to change by mutation. Lack of a corrective replication “proofreading” mechanism results in a very high incidence of spontaneous mutations in RNA viruses, in turn greatly increasing the genotypic variability within each species (“viral qua­sispecies”). Furthermore, a potential for recombination of genetic material is also inherent in the replication process, not only material from different viruses but also from host cell and virus. This factor plays a major role in viral tumor induction and genetic engineering. Functional modifications arising from interactions between different viral species in mixed infections—e.g., phenotype mixing, interference, and complementation—have nothing to do with genetic changes.

Lasting genetic changes in viruses are caused, as in the higher life forms, either by mutation or recombination of genetic material. Temporary nongenetic interactions between viruses in some cases may mimic genetic changes.

Mutation. Mutations are changes in the base sequence of a nucleic acid, re­sulting in a more or less radical alteration of the resulting protein. So-called “silent mutations” (in the second or third nucleotide of a codon) do not in­fluence the amino acid sequence of the protein.

Medically important are mutants with weakened virulence that have re­tained their antigenicity and replication capabilities intact. These are known as “attenuated” viruses. They are the raw material of live vaccines.

Recombination. The viral replication process includes production of a large number of copies of the viral nucleic acid. In cases where two different viral strains are replicating in the same cell, there is a chance that strand breakage and reunion will lead to new combinations of nucleic acid segments or ex­changes of genome segments (influenza), so that the genetic material is re­distributed among the viral strains (recombination). New genetic properties will therefore be conferred upon some of the resulting viral progeny, some of which will also show stable heritability. Genetic material can also be ex­changed between virus and host cell by the same mechanism or by insertion of all, or part, of the viral genome into the cell genome.

Viruses as Vectors

The natural processes of gene transfer between viruses and their host cells de­scribed above can be exploited to give certain cells new characteristics by using the viruses as vectors. If the vector DNA carrying the desired additional gene inte­grates stably in the host cell genome (e.g., retroviruses, adenoviruses, or the ade- noassociated virus), the host cell is permanently changed. This can become the basis for “gene therapy” of certain functional disorders such as cystic fibrosis or parkinsonism. Nonintegrating vectors (alphaviruses, e.g., the Sindbis virus, mengo- virus, or vaccinia virus) result in temporary expression of a certain protein, which can be used, for instance, to immunize a host organism. By this means, wild foxes can be vaccinated against rabies using a vaccinia virus that expresses a rabies virus glycoprotein. Such experimental work must of course always comply with national laws on the release of genetically engineered microorganisms. It must also be men­tioned here that only somatic gene therapy can be considered for use in humans. Human germline therapy using the methods of genetic engineering is generally rejected as unethical

Nongenetic Interactions

In mixed infections by two (or more) viruses, various viral components can be exchanged or they may complement (or interfere with) each other’s functions (phe­notype mixing, complementation or interference). Such processes do not result in stable heritability of new characteristics.

In phenotypic mixing, the genome of virus A is integrated in the capsid of virus B, or a capsid made up of components from two (closely related) virus types is as­sembled and the genome of one of the “parents” is integrated in it. However, the progeny of such a “mixed” virus of course shows the genotype.

In phenotypic interference , the primary infecting virus (usually avirulent( may inhibit the replication of a second virus, or the inhibition may be mutual. The interference mechanism may be due to interferon production or to a metabolic change in the host cell.

In complementation , infecting viral species have genetic defects that render replication impossible. The “partner” virus compensates for the defect, supplying the missing substances or functions in a so-called helper effect. In this way, a defective and nondefective virus, or two defective viruses, can complement each other. Example: murine sarcoma viruses for which leukemia virus helpers deliver capsid proteins or the hepatitis D virus, which replicates on its own but must be supplied with capsid material by the hepatitis B virus.

“Quasispecies.” When viral RNA replicates, there is no “proofreading” mechanism to check for copying errors as in DNA replication. The result is that the rate of mutations in RNA viruses is about 104, i.e., every copy of a viral RNA comprising 10000 nucleotides will include on average one mutation. The consequence of this is that, given the high rate of viral replication, all of the possible viable mutants of a viral species will occur and exist together in an inhomogeneous population known as quasispecies. The selective pres-sure (e.g., host immune system ef f iciency) will act to select the “fittest” viruses at any given time. This explains the high level of variability seen in HIV as well as the phenomenon that a single passage of the attenuated polio vaccine virus through a human vaccine recipient produces neurovirulent revertants.

Occurrence of “new” viral species. It appears to be the exception rather than the rule that a harmless or solely zoopathic virus mutates to b ecome an aggressive human pathogen. In far more cases, changed environmental conditions are responsible for new forms of a disease, since most “new” viruses are actually “old” viruses that had reached an ecological balance with their hosts and then entered new transmission cycles as a result of urbanization, migration, travel, and human incursion into isolated biotopes (examples include the Ebola, Rift Valley fever, West Nile, pulmonary Hanta, and bat rabies viruses).

References

Fritz H. Kayser, M.D. Emeritus Professor of Medical Microbiology Institute of Medical Microbiology, University of Zurich, Zurich, SwitzerlandThieme 2005, Stuttgart ! New York.