KSHV/HHV8, the eighth human herpesvirus, was discovered in applicant's laboratory in 1993. It is associated with three human proliferative diseases ranging from hyperplastic proliferation to neoplasia: Castleman's disease, Kaposi's sarcoma, and primary effusion lymphoma (PEL). These disorders are rarely expressed in the general population, but are common among KSHV seropositive individuals who are immunocompromised, particularly AIDS patients. During the past grant period, the investigators sequenced the viral genome, and discovered and characterized a number of viral genes likely to play a role in KSHV pathogenesis. Their studies have concentrated on latent viral genes expressed in tumor cells that are likely to modify host cell regulatory pathways. By mapping whole genome expression and determining protein expression patterns, they have identified specific viral genes likely to play roles in cell proliferation and prevention of apoptosis in situ. Recently, they have found a latently expressed gene, which is not a component of the previously described major latency transcript locus, LT1 and LT2 encompassing v-cyclin (0RF72) and LANA1 (0RF73). This 1704 bp spliced gene encodes a protein designated latency-associated nuclear antigen (LANA) 2, which is localized to the nucleus and is expressed in all KSHV-infected PEL-derived cells. LANA2 has structural similarities to the IRF4 transcriptional factor present in B cells. This renewal seeks to characterize this latent protein and investigate its potential role in KSHV-related diseases. The four specific aims of this proposal are: 1) to extend the characterization of LANA2 concentrating on the in vivo expression of the protein in KSHV-associated disease tissues, 2) to extend their preliminary studies demonstrating LANA2-mediated upregulation of the CD23 B cell activation antigen, which is also induced by Epstein-Barr virus infection, 3) to identify protein-protein interactions between LANA2 and host cell proteins involved in CD23 transcriptional regulation, and 4) to investigate the potential role of this latent viral gene on cell cycle regulation, apoptosis and in vitro cell transformation. These studies may provide critical insights into the biological role of CD23 signaling in lymphomagenesis and in herpesvirus infection of B cells. Characterization of LANA2 may also contribute to an important future diagnostic and therapeutic target for KSHV infection
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