Diagnosis -- Ganciclovir-resistant Cytomegalovirus (CMV) Infection with UL97 Locus Mutation


Ganciclovir-resistant cytomegalovirus (CMV) infection with UL97 locus mutation.


Antiviral resistance is a potentially life-threatening complication of CMV infections. It is commonly seen in immunocompromised patients with prolonged CMV antiviral therapy. [1]

The esophageal biopsy from this patient demonstrates histopathological findings of viral cytopathic effects with prominent nuclear and cytoplasmic viral inclusions which are highlighted by CMV immunohistochemistry. This is consistent with the patient's clinical history of post-transplant systematic CMV infection despite anti-viral prophylaxis. Viral sequencing study of the UL97 locus detected a population of CMV with A594V mutation and hence the presence of ganciclovir resistant CMV infection.

The genome of CMV is composed of double stranded DNA with a large size of 230kb. The 54th (UL54) and the 97th (UL97) viral open reading frames (ORFs) in the unique long region are important in antiviral drug resistance. [1]

UL97 encodes a protein kinase (pUL97) with conserved serine/threonine kinase functional motifs. The pUL97 kinase phosphorylates ganciclovir (GCV), a crucial step in GCV activation to its effective form, GCV triphosphate. This process is similar to how thymidine kinase phosphorylates and activates acyclovir in HSV1. UL97 mutations account for more than 90% of drug-resistance in CMV infection. [2] Interestingly, although functional pUL97 confers GCV susceptibility, its kinase function is also essential for viral morphogenesis and nuclear egress. Therefore, gene alterations or drugs causing loss of function in pUL97 are inhibitive to viral replication. [3] For instance, maribavir exerts its anti-CMV effect by inhibition of pUL97. As a result, missense mutations involving specific codons (460, 594 and 595) rather than inactivating gene alterations are most commonly encountered clinically, as is exemplified in the current case. [4] Mutations such as A594V most likely confer GCV resistance while retaining other pUL97 functions. UL97 mutations do not affect the actions of cidofovir and foscarnet.

UL54 encodes a virus-specific DNA polymerase (pUL54 Pol) with conserved motifs important for the 3'-5' exonuclease and polymerization functions. pUL54 is the target of GCV, cidofovir and foscarnet. The active form of GCV, GCV triphosphate, and cidofovir are nucleotide analogues that competitively inhibit pUL54. Foscarnet is a pyrophosphate analog and inhibits the pyrophosphate cleavage of dNTP by pUL54. Mutations in UL54 may occur in strains with UL97 mutation and grant the virus cidofovir and foscarnet resistance in addition to stronger ganciclovir resistance. [5] A summary of anti-CMV drug metabolism and targets is illustrated in Figure 3.

Novel therapies can provide alternative routes for treating drug-resistant CMV. Approved by the Food and Drug Administration (FDA) in 2017, letermovir targets CMV terminase to interfere with proper viral DNA cleavage and packaging. [6] Various cell therapies aiming at reconstituting host adaptive immunity against CMV are under development. Some have reached phase III clinical studies and have shown good safety data. [7]


  1. Lurain, N.S. and S. Chou, Antiviral drug resistance of human cytomegalovirus. Clinical microbiology reviews, 2010. 23(4): p. 689-712.
  2. Piret, J. and G. Boivin, Clinical development of letermovir and maribavir: overview of human cytomegalovirus drug resistance. Antiviral research, 2019. 163: p. 91-105.
  3. Prichard, M.N., et al., Human cytomegalovirus UL97 kinase is required for the normal intranuclear distribution of pp65 and virion morphogenesis. Journal of virology, 2005. 79(24): p. 15494-15502.
  4. Campos, A.B., et al., Human cytomegalovirus antiviral drug resistance in hematopoietic stem cell transplantation: current state of the art. Reviews in medical virology, 2016. 26(3): p. 161-182.
  5. Hakki, M. and S. Chou, The biology of cytomegalovirus drug resistance. Current opinion in infectious diseases, 2011. 24(6): p. 605.
  6. Griffiths, P.D. and V.C. Emery, Taming the transplantation troll by targeting terminase. 2014, Mass Medical Soc.
  7. Neill, L. and K. Peggs, Cell therapy for cytomegalovirus infection. Expert opinion on biological therapy, 2020: p. 1-11.

Contributed by Aofei Li, MD, Changqing Ma, MD. PhD, Michael Landau, MD, Octavia M. Peck-Palmer, PhD

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