Human cytomegalovirus (HCMV) is among the most common causes of oral diseases associated with AIDS patients. Persistent and latent infections of HCMV are common in oral cavity. Oral reservoirs of HCMV play an important role in viral transmission and pathogenesis. For example, HCMV infection in oral mucosa, which engages controlled but persistent production and shedding of infectious particles without apparent onset of oral diseases, represents the major source for viral transmission. Understanding the mechanism of HCMV infection in oral mucosa as well as other parts of the oral cavity and eliminating HCMV from its oral reservoirs are central to the prevention of HCMV transmission and its associated diseases. The objective of the proposed research is to study HCMV persistent infection in oral mucosa. We have recently showed that HCMV infection can engage a restrained and controlled production of viral progeny and exhibit no significant cytopathic effect in cultured oral cells and tissues, suggesting that these cultured cells and tissues can be used as the models to study HCMV productive and persistent infections in oral mucosa. Furthermore, preliminary studies have suggested that specific viral proteins block apoptosis and modulate viral gene transcription, leading to the protection and survival of the infected cells and the establishment of controlled but persistent infection in oral mucosa. In the initial part of th proposed study, we will screen a collection of HCMV mutants with deletion of a single viral open reading frame (ORF) to identify viral determinants important for viral productive and persistent infection in oral mucosa. Experiments will then be carried out to study the roles of the identified viral factors in supporting viral infection in oral cells. Furthermore, experiments will also be carried out to investigate how the viral determinants modulate viral gene transcription and inhibit viral-induced apoptosis by interacting with the host transcription machinery and the components of the cellular apoptotic processes in order to achieve successful HCMV persistent infection in oral cavity. These studies will lead to the identification of viral determinants important for vira infection in oral mucosa. Our results will also provide insight into the mechanism of HCMV productive and persistent infection in oral mucosa and facilitate the development of novel strategies for eliminating HCMV infection from its oral reservoirs and for prevention of the transmission and infection of HCMV in oral cavity.