This proposal represents a collaborative project between Dr. Longnecker and Dr. Jardetzky to define the molecular mechanisms involved in Epstein-Barr virus (EBV) entry into B lymphocytes, the major target cell of EBV in human hosts. EBV is associated with a variety of hematopoietic, epithelial, and lymphoproliferative diseases. EBV causes infectious mononucleosis in adolescents and is known to play an etiological role in human malignancies. EBV is a causative agent in endemic Burkitts lymphoma and undifferentiated nasopharyngeal carcinoma (NPC). EBV is also recognized as an important pathogen in immunosuppressed individuals, causing a variety of proliferative disorders including immunoblastic lymphomas, oral hairy leukoplakia, and an unusual tumor of muscle origin in immunosuppressed children. EBV may also be a factor in a variety of other human malignancies including some T-cell lymphomas, Hodgkin's Disease, and breast cancer. These disorders suggest a wide variety of tissue tropism for EBV in vivo. In vitro and in vivo, the cells that are most susceptible to EBV infection and most permissive for viral replication are of B cell origin. The major viral envelope glycoprotein 350 (gp350) binds to the complement receptor type two (CD21) which is abundantly expressed on B cells. Fusion of the virion membrane with the cell membrane minimally requires a complex of viral proteins that includes gp85, gp25, and gp42. Gp42 has been specifically found to bind to human leukocyte antigen (HLA) class II and this interaction is required for EBV entry into B lymphocytes. To date, little is known about the mechanism that EBV uses to bind and penetrate B cells. This proposal will analyze the role of gp42 and its interaction with HLA for viral entry by structure-function studies. Clarifying the interactions between cellular receptors and viral glycoproteins is essential for understanding the tropisms behind EBV associated diseases.
|Effective start/end date||2/22/02 → 11/30/07|
- National Cancer Institute (5 R01 CA093444-05 (REVISED))