Human cytomegalovirus is a ubiquitous herpesvirus that infects greater than 80% of the human population. Like all herpesviruses, HCMV is capable of establishing a life-long infection following primary exposure to the virus. Although HCMV infection is usually sub-clinical in healthy individuals, it is a major health problem for newborns and immunocompromised individuals. HCMV is the most common cause of congenital viral infection in the United States occurring in approximately 1% of all newborn infants. These congenital infections often result in severe mental and motor abnormalities. The other groups of individuals frequently affected by HCMV are immunocompromised individuals, such as AIDS patients and transplant recipients. For example, HCMV has been reported to be the primary cause of death in over 25% of AIDS patients, and is the single most important infectious agent affecting organ recipients. At least two-thirds of organ recipients develop a HCMV infection after transplantation, which often results in organ rejection. The increasing use of therapeutic immunosuppression, organ transplantation, and the incidence of AIDS, has focused attention upon the HCMV life cycle. The goal of the research in this proposal is to provide a better understanding of HCMV replication and specifically, characterize viral transcripts that are packaged within HCMV virions. This proposal is designed to investigate two of these virion RNAs, the 5kb immediate- early (IE) and 1.2kb early transcripts. Two objectives have been outlined; 1) determine if the 5kb IE and 1.2kb early virion RNA transcripts are required during the HCMV life cycle, and 2) identify the mechanism by which virion RNAs are targeted to the HCMV particle. By understanding why and how HCMV packages viral transcripts within virions, novel approaches or therapeutics may be identified to help combat HCMV infection.