ANTIVIRAL DRUG RESISTANCE IN HUMAN CYTOMEGALOVIRUS

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DESCRIPTION: (Adapted from Applicant's Abstract) The problem with treatment of cytomegalovirus (CMV) infection in AIDS patients is that it requires long- term treatment, and, with this treatment, there is emergence of drug resistant virus and disease progression. At present, the monitoring of drug resistance in CMV is limited by classical cell culture techniques which are inefficient and do not provide timely feedback. The purpose of this project is to study the genetic changes that occur in drug-resistant clinical CMV isolates, both as a means of rapid diagnosis and as a quide to the biological characteristics of the resistant viruses. The expectation is that a limited set of mutations in two key CMV genes, the UL97 phosphotransferase (UL97) and in the DNA polymerase (pol), will consistently be associated with drug-resistant viruses, that the evolution of resistance mutations during therapy is associated with treatment failure, and that specific mutations result in cross-resistance to multiple drugs or in altered enzyme activity which may effect viral replication efficiency and, ultimately, virulence. The specific aims of this project are 1) to identify the mutations in UL97 and pol which can confer resistance to anti-CMV drugs in clinical use, e.g., ganciclovir, foscarnet, cidofovir, lobucavir, and acyclovir, 2) to track the evolution of resistance mutations in serial isolates from treated patients in relation to drug regimen, as well as clinical and virological outcome; and 3) to examine the biological properties of drug resistant CMV mutants with respect to cross- resistance, replication competence, genetic stability and alterations in phosphotransferase and polymerase activity. In this regard, the effects of single and multiple mutations will be examined. The work will be performed in the laboratory of Sun Wen Chu at the Oregon Health Sciences University and will utilize clinical isolates provided from the laboratory of Dr. W. Lawrence Drew (UCSF) and from Dr. Alejo Erice (University of Minnesota).