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Chapter: Medical Microbiology: An Introduction to Infectious Diseases: Antibacterial and Antiviral Agents

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Antiviral Resistance

Viral genomes and their replication, as well as the mechanisms of action of the available antiviral agents, have been intensively studied.

ANTIVIRAL RESISTANCE

Viral genomes and their replication, as well as the mechanisms of action of the available antiviral agents, have been intensively studied. Accordingly, an understanding of resistance to antiviral drugs has evolved; investigation of resistance mechanisms has shed light on the function of specific viral genes. For example, it has become clear that a common mecha-nism of resistance to nucleosides (eg, acyclovir, ganciclovir) by herpesviruses are mutations in the viral-induced enzyme responsible for phosphorylating the nucleoside. For herpes simplex virus, this is thymidine kinase, and for CMV, this gene is designated UL97.

Genetic alterations (ie, mutations or deletions) are the basis for antiviral resistance. The likelihood of resistant mutants results from at least four functions:

1.   Rate of viral replication. Herpesviruses, especially CMV and VZV do not replicateas rapidly as HIV and hepatitis B and C. Higher rates of replication are associated with higher rates of spontaneous mutations.

 

2.   Selective pressure of the drug. The selective pressure increases the probability ofmutations to the point that virus replication is substantially reduced.

 

3.   Rate of viral mutations. In addition to viral replication, the rate of mutations differsamong different viruses. In general, single-stranded RNA viruses (eg, HIV, influenza) have more rapid rates of mutation than double-stranded DNA viruses (eg, herpesviruses).

 

4.   Rates of mutation in differing viral genes. For example, within the herpesviruses,the genes for phosphorylating nucleosides (eg, UL97) are more susceptible to muta-tion than the viral DNA polymerase.

 

Resistance to antivirals may be detected in several ways:

Phenotypic. This is the traditional method of growing virus in tissue culture inmedium containing increasing concentrations of an antiviral agent. The concentra- tion of the agent that reduces viral replication by 50% is the end point; it is referred to as the inhibitory concentration (IC50). The IC50 of resistant virus is higher than that of susceptible virus. The degree of viral replication is obtained by counting viral plaques (ie, equivalent to viral “colonies”) or by measuring viralantigen or nucleic acid concentration. Unfortunately, phenotypic assays are very time-consuming, requiring days to weeks for completion. IC50 values increase as the percent of the viral population with the mutation increases.

 

Genotypic. When the exact mutation or deletion responsible for antiviral resis-tance is known, it is possible to sequence the viral gene or detect it with restriction enzyme patterns. These tests are rapid but require knowledge of the expected mu-tation, and they do not provide quantitation of the percent of the viral population harboring the mutation. If only 1 or 5% of the population has the mutation, this result may not be clinically significant when compared to a virus population that is 90% mutated.

 

Viral quantitation in response to treatment. Various methods of quantitatingvirus (eg, culture, polymerase chain reaction, antigen assay) provide a means of assessing the decline of viral titer in response to treatment with an antiviral agent. These assays are rapid and do not require knowledge of the expected mutation. If no decline occurs despite adequate dosage and compliance, viral resistance may be responsible. Likewise, if viral titer initially decreases but subsequently recurs and/or increases, then resistance may have developed.


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