Nucleoside analogues: acyclovir resistance: practice question

A Biochemistry question in the style of the NEET PG paper. Answer it first, then read why the right option is right and why each of the others is wrong.

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Biochemistry · Nucleoside analogues: acyclovir resistance

Sample item

An immunosuppressed patient with a mucocutaneous herpes simplex infection does not respond to intravenous acyclovir, and the isolate is found to lack viral thymidine kinase. Which drug is most appropriate, and why?

Original practice item, not a recalled exam question. Nothing here is recorded.

The answer and the reasoning

B. Foscarnet, which inhibits viral DNA polymerase directly without requiring phosphorylation

Acyclovir is selectively activated by the viral thymidine kinase to the monophosphate and then by cellular kinases to the triphosphate, which terminates viral DNA chains. Thymidine kinase-deficient mutants are therefore resistant to acyclovir and also to its relatives. Foscarnet, a pyrophosphate analogue, binds the polymerase pyrophosphate site directly and needs no activation.

Option by option

  • A. Increased dose acyclovir, to overcome the enzyme deficiency

    Higher acyclovir doses cannot supply an absent activating enzyme, and they add nephrotoxicity.

  • B. Foscarnet, which inhibits viral DNA polymerase directly without requiring phosphorylation (correct)

    Foscarnet acts independently of viral thymidine kinase, so it remains active against these mutants.

  • C. Valacyclovir, which is a prodrug that gives higher levels of acyclovir

    Valacyclovir is converted to acyclovir and so has the same dependence on viral thymidine kinase.

  • D. Famciclovir, which is converted to penciclovir

    Penciclovir also requires viral thymidine kinase for activation, so cross-resistance occurs.

Source note: Original NextPrep sample item — pending expert review. This item is original practice material awaiting independent expert review, so confirm important facts in a standard textbook.

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Questions about this Biochemistry question

What is the answer to this Biochemistry question?

The best answer is B, Foscarnet, which inhibits viral DNA polymerase directly without requiring phosphorylation. Acyclovir is selectively activated by the viral thymidine kinase to the monophosphate and then by cellular kinases to the triphosphate, which terminates viral DNA chains.

Why is "Increased dose acyclovir, to overcome the enzyme deficiency" not the answer?

Higher acyclovir doses cannot supply an absent activating enzyme, and they add nephrotoxicity.

Why is "Valacyclovir, which is a prodrug that gives higher levels of acyclovir" not the answer?

Valacyclovir is converted to acyclovir and so has the same dependence on viral thymidine kinase.

Why is "Famciclovir, which is converted to penciclovir" not the answer?

Penciclovir also requires viral thymidine kinase for activation, so cross-resistance occurs.

What concept does this question test?

It tests Nucleoside analogues: acyclovir resistance in Biochemistry. Thymidine kinase-deficient mutants are therefore resistant to acyclovir and also to its relatives. Foscarnet, a pyrophosphate analogue, binds the polymerase pyrophosphate site directly and needs no activation.

How hard is this question?

We tag it as a multi-step question: it asks you to combine more than one idea. The tag is our own editorial judgement, not an official difficulty rating, so read the reason for every option, not only the answer.

How should I study Nucleoside analogues: acyclovir resistance?

Build one table of enzyme deficiency, disease, inheritance and key finding, then revise it by spaced recall. Then use the flashcards and the other Biochemistry questions on this site to test what stuck.

Is this a real NEET PG question?

No. It is an original practice item (editorial status: sample, version 1). NextPrep does not publish recalled or leaked questions, and independent faculty review of this item has not been completed yet, so confirm important facts in a standard textbook.