Genetic Pathways of Human Cytomegalovirus Drug Resistance

Project: Research project

Description

? DESCRIPTION (provided by applicant): Toxicity and drug resistance limit the efficacy of antiviral therapy for cytomegalovirus (CMV) disease in immunosuppressed hosts such as cancer and transplant recipients. The basic objective of this research is to characterize the viral
mutations and associated mechanisms of resistance to anti-CMV drugs in clinical use, in order to improve the genotypic diagnosis of CMV drug resistance and the selection and development of alternate therapies. For currently licensed drugs (ganciclovir, foscarnet and cidofovir), many resistance mutations and polymorphisms in the CMV UL97 kinase and UL54 DNA polymerase genes have been and continue to be identified and phenotyped, sometimes as mixed subpopulations. Clinical trials of new anti-CMV drugs have recently accelerated, including the UL97 kinase inhibitor maribavir, the terminase inhibitor letermovir, and additional DNA polymerase inhibitors brincidofovir and cyclopropavir. Defining the genetics of resistance and cross-resistance among these compounds is an essential aspect of these new antiviral treatment options. Technical advances in genotyping and recombinant phenotyping are facilitating this research, including efficient mutagenesis of cloned baseline laboratory strains expressing reporter genes for viral quantitation, tagged protein expression systems and next-generation sequencing technology. Specific aims are (1) define the evolution and phenotypes of CMV mutations that develop after in vitro or in vivo exposure to antiviral compounds; (2) elucidate mechanisms of DNA chain extension by which the same exonuclease mutations can confer resistance to some polymerase inhibitors but hypersensitivity to others, and (3) characterize the genetic pathways of resistance to terminase inhibitors with emphasis on mutations in a region of the UL56 gene that confer high-level letermovir resistance.
StatusActive
Effective start/end date8/1/151/31/20

Funding

  • National Institutes of Health: $315,000.00
  • National Institutes of Health: $157,500.00

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Medical Genetics
Cytomegalovirus
Drug Resistance
Antiviral Agents
Mutation
Phosphotransferases
Genetic Crosses
Pharmaceutical Preparations
Foscarnet
Nucleic Acid Synthesis Inhibitors
Exonucleases
Ganciclovir
Immunocompromised Host
DNA-Directed DNA Polymerase
Reporter Genes
Research
Mutagenesis
Genes
Hypersensitivity
Therapeutics

ASJC

  • Medicine(all)
  • Immunology and Microbiology(all)