6. viral genetics/evolution + antiviral drugs

what are the mechanisms of viral evolution? (3)

• genetic drift (gradual)

• genetic shift (abrupt)

• recombination (abrupt)

genetic drift

• point mutations

• error occurs during copying of DNA or RNA, leading to changes in the nucleic acid sequence

• gradual

antigenic drift

amino acid sequence changes due to genetic drift (mutation); will result in a change in the protein or viral antigen

nucleotide insertion/deletion

• may be single nucleotide or larger stretches

• causes frameshift → altered protein sequences, incorrect amino acids

  • dysfunctional, nonfunctional, truncated protein = detrimental to virus

why do RNA viral polymerases have high mutation rates?

more errors due to minimal to no proofreading and editing enzymes

genetic shift

• exchange of viral gene segments between two virus strains to generate a new virus strain

• genetic reassortments

• abrupt

antigenic shift

when genetic shift results in different viral antigens (what immune system will recognize)

what are the two important requirements for genetic shift?

• viral genome has to be segmented

• two related viruses must infect the same host and cell

  • ex. pigs have receptors for both avian and human influenza viruses → act as mixing vessel for influenza viruses

recombination

• an exchange of part of the viral genome with that of another virus

  • splicing genomes

• abrupt

• very common with DNA viruses (can also occur with RNA viruses)

• not the same as reassortment → does not require segmented genomes

recombination can occur between _____

• same type of viruses (ex. two herpesviruses; HSV-1 & HSV-2)

• two different, but related viruses (same family)

what are consequences of viral evolution?

• potential change in fitness

• deleterious mutations = defective replication or less fit virus compared to parent; no survival

• increased virulence

• changes in tropism and transmission efficiency

• immune escape

• drug resistance

what are examples of methods to detect/identify mutations?

• sequencing: sanger and NGS

• antigenic changes: loss in reactivity

  • ELISA: antibodies bind better to wild-type virus (brighter signal); weaker to mutant virus

• phenotypic changes: temperature sensitive mutations

qualities of an ideal antiviral drug

• broad-spectrum antiviral → one drug targets multiple viruses

• minimal toxicity

  • multiple animal species

  • side effects should not cause greater illness than the virus

what are the targets for host-targeting antiviral drugs?

host proteins that are required for the virus life cycle

advantages of host-targeting antiviral drugs

• broad-spectrum potential

• reduced risk of drug resistance

limitations/disadvantages of host-targeting antiviral drugs

• species-specific potential

• greater risks of cellular toxicity → concern targeting host protein; essential for the cell

  • host ribosome — essential for host and virus = not a good target

    • broad-spectrum

    • cellular toxicity

  • host receptor — not completely essential for host

    • not broad-spectrum

    • tolerable

what are the targets for direct-acting antiviral drugs?

any viral protein in any step of the virus life cycle

advantages of direct-acting antiviral drugs

• highly specific/reduced toxicity (RT and RdRp proteins — unique to viruses)

• fast-acting → directly inhibiting a viral process

limitations/disadvantages of direct-acting antiviral drugs

• narrow spectrum

• resistant mutant viruses → can take only 1 mutation to become resistant

  • some viral RNA polymerases have a higher error rate → rapid antiviral resistance

  • however, mutations come at a cost to the virus (gain resistance vs. fitness loss)

what is neuraminidase’s (NA) function (influenza virus)?

during budding, new virions can bind to host cell surface receptors → NA cleaves receptors to release virion → continued infection and replication

how do neuraminidase inhibitors work?

bind NA → NA cannot cleave receptor → budding virion stuck to host cell

how do nucleotide analogs prevent replication?

lack a 3’ OH group → when incorporated into string of nucleotides, polymerases cannot add another nucleotide on → termination of elongation

obstacles to antiviral use in veterinary medicine

• toxicity/bioavailability

  • side effects

  • species differences

• resistance

  • high mutation rates, especially in RNA viruses

• highly specific

  • difficult to create “broad spectrum” drugs

• $ (treatment very costly)