Frequency of Spontaneous Mutations in an Avian Hepadnavirus Infection
| Autor: | Yong-Yuan Zhang, Irmgard Pult, Nathan Abbott, Jesse Summers |
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| Rok vydání: | 2001 |
| Předmět: |
Time Factors
Genotype Immunology Duck hepatitis B virus Genome Viral Viral quasispecies medicine.disease_cause Microbiology Virus Hepatitis B Virus Duck Viral Envelope Proteins Virology medicine Animals Viremia Cloning Molecular Recombination Genetic Genetics Mutation biology cccDNA Hepadnaviridae Infections Models Theoretical biology.organism_classification Resistance mutation Reverse transcriptase Disease Models Animal Ducks Animals Newborn Liver Insect Science Pathogenesis and Immunity Viral genome replication |
| Zdroj: | Journal of Virology. 75:9623-9632 |
| ISSN: | 1098-5514 0022-538X |
| Popis: | In this study, we measured the frequency of revertants of a cytopathic strain of the duck hepatitis B virus that bears a single nucleotide substitution in the pre-S envelope protein open reading frame, resulting in the amino acid substitution G133E. Cytopathic virus mixed with known amounts of a genetically marked wild-type virus was injected into ducklings. Virus outgrowth was accompanied by a coselection of wild-type and spontaneous revertants during recovery of the ducklings from the acute liver injury caused by death of the G133E-infected cells. The frequency of individual revertants in the selected noncytopathic virus population was estimated by determining the ratio of each revertant to the wild-type virus. Spontaneous revertants were found to be present at frequencies of 1 10 5 to 6 10 5 per G133E genome inoculated. A mathematical model was used to estimate that the mutation rate was 0.8 10 5 to 4.5 10 5 per nucleotide per generation. Duck hepatitis B virus (DHBV) belongs to the family Hepadnaviridae, a small group of enveloped viruses which cause persistent liver infections and replicate their DNA genomes through reverse transcription of an RNA intermediate (26). Because of the involvement of reverse transcription, the replication of the viral genome is assumed to be error prone and to give rise to a high degree of genetic variation. In humans, HBV can cause acute and chronic liver disease, and genetic variation is believed to be related to the clinical outcome of hepadnavirus infection (for a review, see reference 8). In recent years, it has become more fully appreciated how the presence of a complex mixture of variants in the virus population within a single host, the quasispecies, may enable rapid adaptation to changing environments (5), in particular to selection forces such as antiviral drugs (1), vaccines (4), immunomodulatory substances (20), and other changes in the host’s immune response, leading to the emergence of various resistance and escape mutants (25). Major mechanisms contributing to the complexity of the viral quasispecies are the generation of errors during viral genome replication, environmentally induced mutations, and recombination. Of these, errors in replication are thought to constitute the greatest source for generating variants. The frequency of replication errors in hepadnaviruses is a function of the fidelities of three polymerization reactions which occur during the life cycle in two different compartments. In the nucleus, covalently closed circular DNA (cccDNA)-templated positive-strand RNA synthesis is carried out by cellular RNA polymerase (RNA pregenome synthesis), and in the viral core particles, RNA-templated negative-strand DNA synthesis and DNA-templated positive-strand DNA synthesis are both carried out by reverse transcriptase. The relative contributions of the various enzymes involved in different polymerization steps to the overall mutation rate of the virus are not known. |
| Databáze: | OpenAIRE |
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