Author

Lu Gao

Date

July 2012

Document Type

Thesis

Degree Name

M.S.

Department

Dept. of Molecular Microbiology and Immunology

Institution

Oregon Health & Science University

Abstract

Kaposi’s Sarcoma (KS) is one of the most popular complications found in human immunodeficiency virus (HIV)-infected patients, which is caused mainly by the KS-associated herpesvirus (KSHV) infection. However, the scarcity of animal models for studying de novo KSHV infection, as well as KSHV-associated diseases greatly hindered these processes, leading to the emergence of using other primate viruses to study the KSHV. Rhesus macaque rhadinovirus (RRV), a monkey γ2 herpesvirus that is closely related to KSHV, shares great genomic and pathogenic similarities with its human counterpart, making it an ideal model to study the KSHV. Both RRV and KSHV encode a cluster of genes with significant homology to cellular interferon (IFN) regulatory factors (IRFs), and these genes were found to be involved in immune signaling, apoptosis, cellular growth and differentiation, resulting in their immune evasion and tumorigenesis. Here we determined that infection of wild type RRV was capable of down-regulating the level of promyelocytic leukemia protein (PML), which is an important intrinsic immune regulatory factor involved in multiple cell signaling pathways. We then further determined that the vIRFs played an important role in RRV-mediated PML down-regulation by comparing the infection of wild type RRV versus vIRF-knock-out RRV. RRV encodes eight vIRFs, making it necessary to figure out which one of the vIRFs is important in the RRV-mediated PML protein down-regulation. We found that, compared to other seven vIRFs, the R12 was the most important factor in interacting with and down-regulating PML protein. Additionally, we found that the RRV- and R12-mediated PML protein down-regulation was proteasome-dependent, and possibly a multi-stage process: the PML protein was aggregated in the nucleus first and then degraded. Moreover, we constructed a telomerized rhesus fibroblast cells-based Tet-ON/OFF system with R12 expression under the control of doxycycline for future applications. Taken together, our findings further demonstrate the significant regulatory effects of RRV vIRFs on host immune system. If these data could be extrapolated to KSHV-associated infections, our findings would suggest that the vIRFs could be potential drug-targets to enhance host immune responses to KSHV infection.

Identifier

doi:10.6083/M44Q7S0G

School

School of Medicine

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