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.

Public Health Relevance

CMV disease is a longstanding management problem in immunosuppressed hosts. Characterizing the viral mutations that confer resistance to existing and new antiviral drugs is important in the genotypic diagnosis of resistance, cross-resistance and the selection of alternate therapy. Detailed understanding of the genetic mechanisms of resistance will improve the ongoing development of additional candidate drugs and antiviral targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI116635-03
Application #
9205483
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Dempsey, Walla L
Project Start
2015-08-01
Project End
2020-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
3
Fiscal Year
2017
Total Cost
$315,000
Indirect Cost
$65,000
Name
Oregon Health and Science University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239