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Antiviral resistance refers to the ability of viruses to evolve and develop mechanisms that render antiviral drugs less effective or completely ineffective. The emergence of resistance can occur due to various genetic and evolutionary processes.

  1. Mutation in the Target Viral Protein:
    • Description: Viruses with high mutation rates, such as RNA viruses like HIV and influenza, are more prone to developing resistance through mutations in the genes encoding viral proteins targeted by antiviral drugs.
    • Example: HIV protease inhibitors, which target the viral protease enzyme, can be rendered less effective due to mutations in the protease gene, leading to changes in the structure of the enzyme and reducing drug binding.
  2. Mutational Escape:
    • Description: Viruses may undergo mutations in regions recognized by the immune system or targeted by antiviral drugs, allowing them to escape immune surveillance or drug inhibition.
    • Example: Influenza viruses can undergo antigenic drift, resulting in changes in the viral surface proteins (hemagglutinin and neuraminidase) targeted by antiviral drugs or the immune system.
  3. Cross-Resistance:
    • Description: Some mutations that confer resistance to one antiviral drug may also confer resistance to other drugs in the same class or with similar mechanisms of action.
    • Example: Resistance to one non-nucleoside reverse transcriptase inhibitor (NNRTI) in HIV may confer cross-resistance to other NNRTIs.
  4. Altered Drug Activation or Metabolism:
    • Description: Resistance can occur if the virus develops mechanisms to alter the activation or metabolism of prodrugs (inactive forms of drugs that are converted to active forms within the host).
    • Example: Resistance to certain nucleoside analogs, like tenofovir, can occur if the virus develops changes that affect the activation of the prodrug form.
  5. Efflux Pump Overexpression:
    • Description: Some viruses can increase the expression of efflux pumps, which are cellular proteins that actively pump drugs out of the infected cell, reducing intracellular drug concentrations.
    • Example: Overexpression of efflux pumps in cells infected with hepatitis C virus (HCV) can reduce the effectiveness of antiviral drugs.
  6. Fitness Cost Compensation:
    • Description: Some resistant mutations may initially reduce the fitness (ability to replicate and spread) of the virus. However, compensatory mutations can arise to restore fitness while maintaining drug resistance.
    • Example: In HIV, resistance mutations in the reverse transcriptase enzyme can be compensated by secondary mutations, allowing the virus to replicate efficiently despite the presence of the drug.
  7. Viral Quasispecies:
    • Description: Many RNA viruses exist as quasispecies, populations of genetically diverse variants. A subset of these variants may carry mutations conferring resistance.
    • Example: HCV quasispecies can harbor drug-resistant variants, and treatment with direct-acting antivirals can select for resistant variants within the quasispecies.
  8. Poor Adherence to Treatment:
    • Description: In some cases, the development of resistance is associated with inadequate adherence to the prescribed antiviral treatment, allowing the virus to replicate in the presence of suboptimal drug concentrations.
    • Example: Poor adherence to the prescribed dosing schedule of antiretroviral drugs in HIV treatment can contribute to the development of resistance.

 

Why is HIV hard to treat?

  • Mutations in the active site of reverse transcriptase
  • These changes selectively block the binding of the drug to DNA but allow other nucleotides to be added

 

How did resistance develop?

  • HIV reverse transcriptase is very error-prone
  • About half of all DNA transcripts produced contain an error (mutation)
  • HIV has the highest mutation rate (3 x 10−5 per nucleotide base per cycle of replication)
  • There is thus enormous VARIATION in the HIV population in a patient
  • qNATURAL SELECTION now starts to act in the presence of the drug where certain variants are better able to survive and reproduce than others
  • These variants produce more offspring and contribute more copies of their genes to the next generation