Ganciclovir activation by CMV UL97 kinase and resistance
Ganciclovir is a prodrug (inactive until changed) that cytomegalovirus (CMV) activates with its UL97 kinase (an enzyme adding phosphate groups), so UL97 mutations cause ganciclovir resistance.
Remember
CMV has no thymidine kinase, so ganciclovir needs the viral UL97 kinase to switch it on. When a UL97 mutation causes ganciclovir resistance, switch to foscarnet (or cidofovir), which does not need UL97 activation.
Memory aid
UL97 is the key that unlocks ganciclovir, so a faulty key leaves the drug locked and switched off.
Use the key picture to remember that ganciclovir stays switched off when UL97 is faulty.
Ganciclovir is a nucleoside analogue (a drug that mimics a building block of DNA). It is given as an inactive prodrug, meaning it must be changed before it works. Valganciclovir is its oral prodrug (a form that the body converts into ganciclovir).
Adding phosphate groups is called phosphorylation, and the enzyme that does it is a kinase. Other herpesviruses, herpes simplex and varicella zoster viruses, make their own thymidine kinase, a viral enzyme that adds the first phosphate to aciclovir, the drug used for them. Cytomegalovirus (CMV) has no thymidine kinase of its own. Instead, a different viral kinase encoded by the UL97 gene adds the first phosphate to ganciclovir inside infected cells. Ordinary host cell kinases (normal human enzymes) then add the second and third phosphates. The resulting triphosphate inhibits the viral DNA polymerase (the enzyme that copies viral DNA).
A UL97 mutation therefore leaves less ganciclovir activated, so the virus keeps replicating despite treatment. UL97 mutations are the commonest cause of ganciclovir resistance, and UL54 (DNA polymerase) mutations can also contribute.
The usual next step is a different drug that does not need UL97, such as foscarnet or cidofovir. Foscarnet blocks the viral DNA polymerase directly, so it remains active against ganciclovir-resistant CMV caused by UL97 mutations. Both are nephrotoxic (damaging to the kidneys).
Ganciclovir and valganciclovir are also more myelosuppressive than aciclovir (they can suppress the bone marrow, where blood cells are made), so they are reserved for serious CMV disease.
Key facts
- Activation
- in CMV-infected cells, the viral UL97 kinase adds the first phosphate to ganciclovir.
- Contrast
- herpes simplex and varicella zoster viruses use thymidine kinase to activate aciclovir, but CMV has no thymidine kinase of its own.
- Target
- the activated triphosphate inhibits the viral DNA polymerase, so that enzyme is the drug target, not the activator.
- Resistance
- UL97 mutations are the commonest cause of ganciclovir resistance, and UL54 (DNA polymerase) mutations can also contribute.
- Next step
- foscarnet and cidofovir do not need UL97, but both are nephrotoxic.
- Toxicity
- ganciclovir and valganciclovir are myelosuppressive, so they are reserved for serious CMV disease.
Exam traps
- Loss of thymidine kinase is not the cause of ganciclovir resistance in CMV, because CMV has no thymidine kinase of its own and uses the UL97 kinase instead.
- Viral DNA polymerase is the target that the activated triphosphate form of ganciclovir blocks, not the enzyme that activates the drug.
- Aciclovir is not a useful switch for ganciclovir-resistant UL97 mutants, because it has weak activity against CMV and these mutants tend to be cross-resistant (also resistant to aciclovir).
Read the full notes
Tested in 6 SimpleMed+ questions
Practice it in Pharmacology, with the answer and a full explanation after every question.
Practice these questions