Virus Genetics Flashcards
Types of virus genomes
- DNA or RNA but not both
- single or double stranded
- single stranded RNA can be segmented or nonsegmented
- linear or circular
Size of viruses
- Parvoviruses- 2 genes
- Retroviruses- 3 genes
- Papillonaviruses- about 8 genes
- Adenoviruses- about 10 genes
- Herpes viruses- 70 genes and more
- Pox viruses- 200 genes
viruses have too few genes to survive independently, and depend on cellular genes to supply the missing functions
Gene expression in viruses
- regulated by cellular transcription factors
- Papillomavirus gene expression is regulated by keratinocyte factors, thus making the virus skin specific
Viruses are efficient
- no space is wasted
- 100 percent of genome encoding protein or tRNA
- reading frames can overlap
- ribosomal frame shifting- known as translational frameshifts, due to ribosome slipping 1 or 2 bases on RNA
- alternative splicing of RNA
- cleavage of polyproteins by viral proteases (drug target)
Genome structures
- simple genomes- Retrovirus- genes linear on one RNA strand, with one promoter
- complex genomes- adenoviruses, herpesviruses, poxviruses- genes on both strands of DNA, often over lapping and each with its own promoter
Virus high mutation frequency
- high error rate of polymerase
- lack of proofreading and error correction
- lack of second strand in some viruses
-all types of mutations: point mutations, deletions, insertions, recombinations and rearrangements, insertion to host cell genome
Virus mutations
- allow epidermiological studies
- can allow live vaccines to be made
- can produce new antigens which avoid immunity
- can lead to drug resistance
- integration of viral genome can cause disease
Complementation
when a gene function of one virus replaces a mutated gene of another. Allows defective viruses to replicate and express their genes. Allows cell lines to support vaccine productio
Phenotype mixing of similar viruses
- exchange of capsid proteins
- if two polio virus serotypes infect the same cell the progeny might have capsids that are a mix of each serotype
Pseudotype virus
-the genetic material of one virus in the capsid or envelop of another
Recombination of homologous viruses
-the exchange of genes by crossing over at regions of homology. Produces a hybrid virus which reproduces- Western equine encephalitis virus
Reassortment of segmented viral genomes
- the rearrangement of parts of a segmented genome to form a new set of segments
- eg infuenza virus- antigenic shift
- reovirus (adenovirus)
Virus interference
- infection by one virus tends to prevent infection by another by:
- blocking of receptors
- competition for resources
- production of interferon or other anti-viral agents
Viral insertion mutations
-when a virus inserts like HIV it can interrupt the normal host genome and affect transcription in this way too
Development of Gene Therapy Viruses
- deletion of essential gene- insert that gene into packaging cell
- clone the therapeutic gene to virus
- grow the virus in the packaging cell
- test in cells- animals- humans
Diseases that might be treated by gene therapy
- hemophilia
- immune deficiencies
- retinal disorders
- liver enzymes deficiencies
- cystic fibrosis
- cancer: tumor suppressor genes, silencing of oncogenes, immune response genes, toxic or suicide genes, replicating cytotoxic viruses
Delivery of gene therapy by certain viruses
-delivery of gene therapy by viruses requires mutants whose replication is severely restricted
-they can be made from:
Retroviruses (mouse viruses, or HIV)
Adenoviruses
Herpes Simplex Virus
Adeno-associated virus
Problems with gene therapy
- short/ transient expression of foreign gene
- low efficiency of gene transfer
- inflammation in response to the virus- requirement for very high doses of virus vectors
- potential for chromosomal disturbances by virus
Gene therapy virus side effects
- Jesse Gelsinger- ornithine transcarbamylase deficiency, clinical trial with OTC in adenovirus into hepatic artery, developed acute respiratory distress syndrome
- Jolee Mohr, adalimumab, AAV/TNF blocker into knee died of systemic histoplasmosis
- SCID-X1, mouse leukemia virus modified to transduce stem cells, some developed T cell leukemia
Future research on gene therapy
- mutated viruses that cause less imflammation
- viruses that target a specific tissue
- conditionally replicating viruses
- non-viral methods of transfer of genes
