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Published on: October 5, 2015
Dynamics and Evolution of Donor-derived Cytomegalovirus Infection in 3 Solid Organ Transplant Recipients With the
Fien Horsten1, Sunwen Chou2, Sarah Gillemot1
1Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute, KU Leuven, Leuven, Belgium.
Background:
Cytomegalovirus (CMV) infection poses a significant risk to immunosuppressed transplant recipients, manifesting through primary infection, reinfection, or reactivation.
Methods:
We analyzed the emergence of drug resistance in CMV infection in 3 patients who were later found to have received an allograft from a shared, deceased donor. The seronegative transplant recipients developed symptomatic CMV infections after bowel/pancreas, kidney, or lung transplantation. Prospective Sanger sequencing was used to identify mutations in the viral DNA polymerase (DP) and protein kinase (PK). DP and PK variants were retrospectively quantified by targeted next-generation sequencing. The impact of the novel DP-A505G substitution on drug susceptibility was assessed using a recombinant virus. Whole-genome sequencing of clinical CMV samples was enabled through target DNA enrichment.
Results:
The DP-A505G substitution was found in all patient samples and could be associated with a natural polymorphism. A subsequent review of the patients' clinical histories revealed that they had all received organs from a single donor. The CMV infection exhibited divergent evolution among the patients: patient 1 developed resistance to ganciclovir and foscarnet because of 2 DP mutations (V715M and V781I), patient 2 showed no genotypic resistance, and patient 3 developed ganciclovir (PK-L595S) and maribavir resistance (PK-T409M). Interpatient variation across the entire CMV genome was minimal, with viral samples clustering in phylogenetic analysis.
Conclusions:
All 3 transplant recipients were infected with the same donor-derived CMV strain and readily developed different drug susceptibility profiles. This underscores the importance of judicious antiviral drug use and surveillance in preventing antiviral resistance emergence.
Insights
Three transplant recipients infected with the same cytomegalovirus (CMV) strain developed varied drug resistance profiles. This highlights the need for careful antiviral use and monitoring in transplant patients to prevent resistance.
Area of Science:
- Virology
- Immunology
- Transplant Medicine
Background:
- Cytomegalovirus (CMV) infection is a major threat to transplant recipients, leading to primary infection, reinfection, or reactivation.
- Immunosuppression in transplant recipients increases susceptibility to severe CMV disease.
Purpose of the Study:
- To investigate the emergence of drug resistance in cytomegalovirus (CMV) infections among transplant recipients.
- To analyze the genetic basis of antiviral resistance in CMV strains originating from a shared donor.
Main Methods:
- Analysis of CMV drug resistance in 3 patients who received organs from a single deceased donor.
- Identification of mutations in viral DNA polymerase (DP) and protein kinase (PK) using Sanger sequencing.
- Quantification of DP and PK variants via targeted next-generation sequencing and assessment of a novel DP-A505G substitution's impact on drug susceptibility.
Main Results:
- A DP-A505G substitution was detected in all patient samples, potentially linked to natural polymorphism.
- CMV infections showed divergent evolution, with patients developing distinct resistance patterns: ganciclovir/foscarnet resistance (2 DP mutations), no genotypic resistance, and ganciclovir/maribavir resistance (PK mutations).
- Minimal interpatient variation across the CMV genome was observed, with samples clustering phylogenetically, indicating a common origin.
Conclusions:
- All 3 patients were infected with the same donor-derived CMV strain but exhibited different drug susceptibility profiles.
- Judicious antiviral drug use and vigilant surveillance are crucial for preventing the emergence of antiviral resistance in transplant recipients.
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