Treatment for Viral Infection
Despite the fact that viruses use the machinery of the host, their method of operation can be different. Most antiviral drugs are nucleoside analogues which inhibit viral polymerases. Many viral polymerases are less specific for substrate than are host enzymes. The viral polymerase will bind a nucleotide analogue with modifications of the base and/or sugar much better than the host enzyme. These drugs prevent chain elongation or proper recognition and base pairing.
Resistence to drugs can come about by selective pressures that lead to the emergence of mutant viruses. These selective pressures include (1) the immune response, (2) antiviral drugs and (3) opportunity to survive in new species (emerging infections). Mutations are more frequent in viruses due to the lack of proofreading function of their viral RNA and DNA polymerases. Some mutations that occur include the following:
- point mutations which typically lead to a gradual alteration of antigenic eptiopes or targets of antiviral drugs without loss of the primary function of the gene.
- deletions are observed only in non-essential viral genes (e.g., strains which lack thymidine kinase).
- homologous recombination occurs between genomes of genetically similar viruses. (e.g., HIV and SIV can recombine)
- genomic reassortment takes place when two segmented viruses infect the same cell and is unique to viruses.
Drugs which target the following processes have been effectively used against viruses.
- Non specific: interferons Virus infection and/or dsRNA induces IFN production and secretion. IFN binds to its receptor and induces STAT transcription factors leading to inactivation of elongation factor, RNAse induction and inhibition of cell proliferation.
- Uncoating: Uptake of many viruses utilize the acidic environment of the endocytic vesicle to initiate uncoating. Drugs like amantidine (which is effective against influenza A) can neutralize these compartments and inhibit virion uncoating.
- Genome replication: Antiviral drugs that cause termination of the DNA chain due to modified nucleoiside sugar residues include Acyclovir (used against herpes viruses that encode a thymidine kinase; the kinase activates the drug by phosphorylation. No initial phosphrylation occurs in uninfected cells) and ganciclovir (used against CMV). dideoxyinosine (DDI) and AZT are dideoxynucleotides that inhibit reverse transcription. Newer non-nucleotide non-substrate analogs like nevirapine bind and inhibit the HIV RT.
- mRNA synthesis: Ribavirin is an analog of the nucleoside guanosine and inhibits nucleoside biosynthesis and mRNA capping.
- Protein processing: Protease inhibitors like Saquinavir have been effective against HIV which needs a protease to chop up long transcripts.
