This international collaboration is intended to improve the genetic characterization of drug resistance in human cytomegalovirus (CMV). In subjects with AIDS or other long term immunosuppression, CMV disease such as retinitis tends to be a relapsing condition that eventually progresses despite maintenance antiviral therapy. At present it is not clear how often disease progression is due to host or pharmacokinetic factors and how often it is due to mutations in CMV that cause drug resistance. The principal investigator and collaborator, working with drug-resistant isolates from their respective geographic sites, have identified many of the mutations in the UL97 phosphotransferase and DNA polymerase (Pol) genes of CMV that are so far known to be involved in drug resistance. The UL97 mutations that confer ganciclovir resistance are now fairly well defined, but resistance mutations in Pol, which have the potential to confer multi-drug resistance, are less well studied. The evolution of drug resistance mutations in treated subjects, and the associated changes in viral load and phenotype at various body sites, need to be better defined to guide clinical practice. The proposed contribution of serial specimens, isolates and diagnostic techniques from an established referral lab in Italy should result in an earlier answer to several important remaining questions.
The specific aims of this collaboration are: 1. Monitor immunocompromised patients with CMV disease for clinical and virologic variables that predict drug resistance, and select specimens for detailed analysis of viral drug resistance markers. 2. Develop improved methods for the rapid phenotypic assay of drug resistance suitable for use in monitoring a course of antiviral therapy. 3. Genetically characterize CMV isolates form patients undergoing antiviral therapy, as to variability of the viral population within and between different body sites, the presence of mutations that confer drug resistance, and the biological properties of mutant viruses.
