Herpesvirus latency depends on viral replication. Progeny viruses are needed to pass on new viral infections, and for Kaposi sarcoma-associated herpesvirus (KSHV), a certain level of replication appears to be required to maintain the latent state. Herpes simplex virus (HSV-1) in neuronal ganglia can cycle between latent and replicative states. Epstein Barr virus (EBV) infection results in mononucleosis, which provides a reservoir of latently infected cells in which the EBV genome resides as a latent episome. EBV is associated with several human cancers including nasopharyngeal carcinomas and Burkitts lymphoma. KSHV infection leads to Kaposi's sarcoma, primary effusion lymphoma, and Multicentric Castleman's disease. Our working hypothesis is that to understand the establishment and maintenance of herpesvirus latency we must understand the role of viral replication and recombination factors as well as the proteins which directly control the latent origins. Central to these pathways are the molecular complexes formed between the viral DNAs and proteins. Our efforts are focused on elucidating molecular mechanisms and structures related to viral DNA-protein interactions. This can provide insights that drive new thinking and uncover important mechanistic details.
In Aim I we will examine the structure of filaments generated by the multifunctional DNA binding proteins of HSV-1, EBV, and KSHV. Our working hypothesis is that these filaments provide structural scaffolds upon which replication and recombination occur in the infected cell nucleus and this will be tested using a combination of biochemical, genetic and and electron microscopic (EM) approaches.
In Aim II, the structure of the 2-part recombinases of the herpesviruses will be examined using biochemical and electron microscopic methods. Their action on the KSHV terminal repeats will be examined to determine if this may lead to circularization and latency.
In Aim III the binding of KSHV LANA origin binding protein together with p53 and other host proteins will be examined using EM to learn how these proteins remodel the architecture of the latent origin. These studies are highly interactive with the KSHV work being done together with the Dittmer and Damania laboratories.
These studies will generate unique the structural and biochemical information needed to provide the basis for a new understanding of the molecular basis for latency and lytic replication in the herpesviruses at the level of DNA-protein complexes. These results will, in turn, provide new inroads and thinking that are needed to generate anti-viral approaches.
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