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Difficulty: MediumInfectious Disease Mechanisms

A 45-year-old man who received a deceased-donor renal allograft 6 months ago presents to the clinic with decreased visual acuity and floaters in his right eye. Funduscopic examination reveals perivascular yellowish-white retinal exudates with associated intraretinal hemorrhage. He is admitted and started on induction therapy with an appropriate intravenous antiviral agent. Three weeks later, his symptoms worsen, and laboratory testing shows a rising viral load of the causative pathogen, suggesting drug resistance. The most common mechanism of resistance for this specific antiviral agent involves a genetic mutation that prevents the initial intracellular activation of the drug. The mutated gene most likely encodes which of the following viral enzymes?

  1. Protein kinaseAnswer
  2. B
    Thymidine kinase
  3. C
    DNA polymerase
  4. D
    RNA-dependent RNA polymerase
  5. E
    Viral protease

Answer

Protein kinase
Cytomegalovirus (CMV) retinitis is typically treated with ganciclovir, a guanosine analog that ultimately inhibits viral DNA synthesis. However, ganciclovir is administered as a prodrug that must first be phosphorylated into a monophosphate form within the infected cell. Unlike Herpes Simplex Virus (HSV) and Varicella-Zoster Virus (VZV), which use a viral thymidine kinase for this initial step, CMV does not encode a functional thymidine kinase. Instead, CMV utilizes a viral protein kinase encoded by the UL97 gene. The most common mechanism of ganciclovir resistance in CMV involves a genetic mutation in the UL97 gene, which directly prevents this crucial initial phosphorylation, rendering the drug inactive.

Step-by-Step Solution

1
Diagnose the opportunistic infection based on the clinical presentation.
The patient is a transplant recipient presenting with visual changes and funduscopic findings of retinal exudates with hemorrhage ('pizza pie' retinopathy), which is highly characteristic of Cytomegalovirus (CMV) retinitis.
Establishing the correct pathogen is necessary to identify the appropriate standard therapy.
2
Identify the standard first-line therapy for this infection.
The standard induction therapy for sight-threatening CMV retinitis is intravenous ganciclovir.
The question asks about the mechanism of resistance to the initial antiviral agent used.
3
Determine the intracellular activation pathway of the identified drug and the mechanism of resistance described in the stem.
Ganciclovir is a prodrug that must be phosphorylated to become active. In CMV, this first phosphorylation step is catalyzed by a viral protein kinase encoded by the UL97 gene. Mutations in this gene prevent the drug's activation.
The stem specifies a mutation preventing the 'initial intracellular activation of the drug,' isolating the activating enzyme rather than the final target.

Key Concept

Cytomegalovirus (CMV) resistance to ganciclovir most commonly occurs via mutations in the viral UL97 gene, which encodes a protein kinase responsible for the initial phosphorylation and activation of the drug.
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Topics

Infectious Disease Mechanisms

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