Antiviral Drug Resistance in Human Cytomegalovirus

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DESCRIPTION (provided by applicant): Drug resistance limits the efficacy of long-term antiviral therapy for cytomegalovirus (CMV) disease in severely immunosuppressed hosts. Although the advent of combination antiretroviral therapy has reduced the frequency of invasive CMV disease, it continues as a problem in those failing anti-HIV therapy and in transplant recipients who develop primary CMV infection. In the past few years we have developed a reasonable understanding of the common mutations in the CMV UL97 phosphotransferase and UL54 DNA polymerase genes that confer resistance to the current systemic anti-CMV drugs ganciclovir, foscarnet and cidofovir. This information is already widely used for genotypic diagnosis of CMV resistance. Some gaps in our knowledge remain. There are probably additional mutations in UL97 and UL54, or in other viral genes involved in DNA replication, that confer varying degrees of drug resistance or growth adaptation. The combined effects of multiple mutations have not been well characterized. Specific resistance mutations seem to confer varying degrees of resistance to the same drugs when assessed in different viral genetic backgrounds. Phenotypic assays for CMV growth and drug resistance need to be improved. A newer anti- CMV benzimidazole L-riboside drug, maribavir, appears to have the advantages of potency, oral bioavailablility, low toxicity in early clinical trials, and different mechanisms of antiviral action involving the direct inhibition of UL97. Maribavir-resistant CMV strains have been found with mutations in their UL97 or UL27 genes. The available information hints at the complexity of the virion assembly stage of viral replication, and its potential as an antiviral target. The specific aims for the upcoming period remain (1) to study additional viral mutations that affect resistance and cross-resistance to current anti-CMV drugs, by transfer of the mutations to reference CMV strains, (2) investigate the phenotypic effects of single and multiple mutations on different viral genetic backgrounds, and (3) determine the genetic basis of CMV resistance to maribavir. Experimental priorities include the development of efficient, diagnostically useful approaches for constructing and phenotyping recombinant viruses containing specific mutations, and defining the presently unknown function of the CMV gene UL27 which was recently found to be mutated in several maribavir-resistant viruses.