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Difficulty: HardInfectious Disease Mechanisms

A 4242-year-old man comes to the clinic due to a two-week history of fatigue, fever, and progressive shortness of breath. He underwent a deceased-donor renal transplantation six months ago and is currently taking tacrolimus, mycophenolate mofetil, and prednisone. His temperature is 38.2∘C38.2^\circ\text{C} (100.8∘F100.8^\circ\text{F}). Physical examination reveals coarse crackles in bilateral lung bases. Laboratory testing shows a leukocyte count of 2,400/mm32,400/\text{mm}^3 and serum creatinine of 1.6 mg/dL1.6 \text{ mg/dL}. Chest radiography demonstrates bilateral interstitial infiltrates. Quantitative polymerase chain reaction testing of the patient's blood is markedly positive for an enveloped, double-stranded DNA virus. Intravenous ganciclovir therapy is initiated. Three weeks later, the patient's clinical condition has not improved, and a repeat viral load remains elevated. Genotypic testing confirms resistance to the administered antiviral medication. Which of the following is the most likely cellular mechanism responsible for this pathogen's drug resistance?

  1. Impaired initial phosphorylation of the medicationAnswer
  2. B
    Structural mutation in a viral thymidine kinase
  3. C
    Decreased binding to the viral RNA-dependent RNA polymerase
  4. D
    Enhanced drug efflux via ATP-binding cassette transporters
  5. E
    Increased renal clearance due to host cytochrome P450 induction

Answer

Impaired initial phosphorylation of the medication
The correct answer identifies the primary mechanism of ganciclovir resistance in Cytomegalovirus (CMV). Ganciclovir is a nucleoside analog that acts as a false substrate for viral DNA polymerase, halting viral replication. To become active, it must undergo three stages of phosphorylation. The first, rate-limiting phosphorylation step is catalyzed by the viral UL97 protein kinase. The most common cause of ganciclovir resistance in clinical practice is a mutation in the UL97 gene, which impairs this initial phosphorylation step and prevents the drug from becoming active.

Step-by-Step Solution

1
Identify the infectious pathogen based on the clinical vignette.
The patient has Cytomegalovirus (CMV) infection.
The patient is 66 months post-renal transplant with pneumonitis, leukopenia, and a positive PCR for an enveloped, double-stranded DNA virus. This is the classic presentation and virologic profile of CMV.
2
Identify the primary mechanism of action of the administered medication.
Ganciclovir requires triphosphorylation to actively inhibit viral DNA polymerase.
Ganciclovir is a guanosine analog prodrug. The critical first phosphorylation step is catalyzed by the CMV-specific UL97 protein kinase, followed by two additional phosphorylations by host cellular kinases.
3
Determine the mechanism of resistance to the medication.
The pathogen has a mutation preventing the initial phosphorylation step.
The most common mechanism of CMV resistance to ganciclovir is a mutation in the UL97 gene, which results in a defective viral protein kinase that cannot perform the initial phosphorylation, rendering the drug inactive.

Key Concept

Cytomegalovirus (CMV) resistance to ganciclovir is most frequently caused by a mutation in the viral UL97 protein kinase, preventing the initial phosphorylation step required to activate the nucleoside analog.
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Topics

Infectious Disease Mechanisms

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