The Kaposi's sarcoma associated herpes virus (KSHV/HHV-8) is a gammaherpesvirus associated with human malignancies including Kaposi's sarcoma and body cavity based lymphomas (BCBLs) or Pleural Effusion Lymphomas (PELs). One of the latency-associated nuclear antigen (LANA) is constitutively expressed in all latently infected KSHV cells and is incloved in the maintenance of the KSHV genome as well as transcriptional regulation. Recent studies has also shown an important role in regulation of vial latency in association with the viral immediate early transactivator Rta. Studies from our group and others have shown that LANA binds to cis-acting elements withing the KSHV terminal repeats (TR) and associated with a number of chromosomal proteins. Additionally, LANA can induce chromosomal aberations when expressed in human cells in vitro suggesting a role for LANA in induction of oncogenesis in KSHV infected cells.
The specific aims of this proposal will continue to focus on studies of KSHV latent replication in a LANA dependent and independent mode.
Specific aims will focus on 1) The identification and characterization of specific sites within the KSHV genome capable of initiating KSHV latent replication;2) Determine the role of LANA and other cellular proteins in terms of the dynamics of protein-DNA interactions at these sites of latent replication for firing of these replication initiation sites;and 3) Genetic analysis of LANA and these replication initiation sites for determination of the role of the cis and trans acting factors during the initial stages of infection and maintenance of KSHV latent replication.
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