Status of Cytomegalovirus Prevention and Treatment in 2000

Cytomegalovirus (CMV) infection continues to be a problem in selected populations following hematopoietic stem cell transplantation (SCT). Although there have been no new antiviral agents for management of this infection in recent years, the methods for using the existing agents have improved with newer assays for detection of virus. In addition, our understanding of immunity to CMV has undergone considerable expansion. This paper will address these new aspects relating to CMV infection in the setting of SCT. In Section I Dr. Zaia reviews the pathogenesis of CMV and the current epidemiology of CMV disease following marrow or blood allo-SCT with emphasis on late-onset disease. The current lab tests available for preemptive management are summarized including the role for conventional shell vial cultures, and a comparison of the CMV antigenemia assay with the new nucleic acid-based assays, including the hybrid capture assay, the NASBA assay, and "real-time" PCR assays. Use of antiviral agents with these tests in the preemptive management of CMV infection is discussed. Ultimately, what is necessary is restoration of adequate CMV immunity, and that requires understanding the basics of the CMV-specific immune response. In Section II, Dr. Sissons traces the evolution of the CTL response from primary infection into memory and reviews recent advances in the understanding of cytotoxic T cell based immunity to CMV, based on the use of T cell clonotypic analysis and markers of T cell memory and activation, with conventional CTL functional assays. In Section III Dr. Riddell presents approaches to correction of the problem of CMV pathogenesis, namely direct restoration of the CMV-specific cellular immune deficiency. Attempts at passive therapies will be reviewed with the focus on current problems and approaches to these problems. In Section IV, Dr. Diamond presents work on the identification of multiple HLA-allele specific cytotoxic T cell epitopes specific for CMV-pp65 and - pp150. Specific epitopes are recognized by CMV-seropositive individuals including healthy donors, SCT recipients, and AIDS patients, indicating their potential usefulness as vaccines. One of these epitopes is recognized by most individuals who express the HLA A(*)0201 Class I allele. Pre-clinical evaluation in HLA2.1 transgenic mice of vaccine structures utilizing this epitope, and alternative delivery systems are described. Possible methods for vaccination of donor and/or recipient of a SCT as well as their limitations, utilizing synthetic or viral vaccines, are discusseed.