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The 11 th International Workshop on KSHV & Related Agents, Birmingham, UK Pathogenesis Abstract 14 GENERATION OF RHESUS RHADINOVIRUS LACKING EXPRESSION OF VGPCR AND VCD200 FOR THE ASSESSMENT OF THEIR ROLES IN DISEASE DEVELOPMENT IN A RHESUS MACAQUE MODEL OF KSHV INFECTION Ryan D. Estep 1 , Elisa Cardenas 3 , and Scott W. Wong 1,2,3 Vaccine and Gene Therapy Institute1 , Oregon Health & Science University West Campus, Division of Pathobiology and Immunology2 , Oregon National Primate Research Center, Beaverton, Oregon 97006; Department of Molecular Microbiology and Immunology3 , Oregon Health & Science University, Portland, Oregon 97201. Abstract RRV strain 17577, the rhesus macaque homologue of KSHV, was recently cloned as an infectious Bacterial Artificial Chromosome (BAC). The RRV BAC system allows for the rapid genetic manipulation of the RRV genome in bacteria, and the subsequent production of modified forms of RRV. Currently, we are using the RRV BAC system to modify genes that have been proposed to be important in the development of disease associated with KSHV infection in humans. KSHV and RRV both encode a viral G proteincoupled receptor (vGPCR) and viral CD200 homologue (vCD200), proteins which possess oncogenic and immunomodulatory functions, respectively. Although extensively analyzed in vitro, the roles that the KSHV and RRV vGPCR and vCD200 proteins play during a de novo infection in vivo are currently unknown. Therefore, we have used the RRV BAC system to disrupt expression of the vGPCR and vCD200 proteins in RRV, through the insertion of specific stop mutations in ORF74 and R15. Thus far, we have successfully generated viruses that no longer express these proteins during infection, and preliminary analyses indicate that viruses devoid of vGPCR or vCD200 expression possess similar growth properties to wild-type RRV in vitro. Other ongoing studies with these viruses include examination of the effects of vGPCR and/or vCD200 expression on virus-induced signaling and immunoregulatory properties in vitro, and importantly, how lack of these proteins may affect the development of viral-induced disease in vivo. Further plans include the generation of chimeric versions of RRV expressing KSHV vGPCR and/or vCD200. Presenting author Email: estepr@ohsu.edu 36
The 11 th International Workshop on KSHV & Related Agents, Birmingham, UK Pathogenesis Abstract 15 GENERATION OF VFLIP TRANSGENIC MICE: A MODEL TO STUDY KSHV- ASSOCIATED LYMPHOMAGENESIS Gianna Ballon 1 , Amy Chadburn 1 , Yi-Fang Liu 1 , Yoshiteru Sasaki 2 , Klaus Rajewsky 2 , Ethel Cesarman 1 1 Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10021, USA 2 CBR Institute for Biomedical Research, Harvard Medical School, Boston, MA 02115, USA Abstract Primary effusion lymphoma (PEL) is a distinct subtype of aggressive non-Hodgkin’s lymphoma (NHL), specifically associated with infection by Kaposi's sarcoma-associated herpesvirus (KSHV). Several in vitro observations suggest that vFLIP, a protein expressed during latency, is an important viral oncogene. It is essential for the survival of KSHV-infected PEL cells, mainly by constitutively activating the NF-kB pathway. In order to assess the role of vFLIP in the pathogenesis of PEL, we developed transgenic mouse models expressing vFLIP in B-cells. The experimental approach used has been a conditional recombinant activation of vFLIP, by using the ROSA26 knock-in system. A specifically restricted expression of the transgene in CD19+ B-cells has been achieved by crossing the ROSA26.vFLIP knock-in mice with other mice expressing cre recombinase under the control of the CD19 promoter. These mice have also been crossed with the LANA transgenic mice to assess a potential synergistic effect between these two KSHV latent proteins in the lymphomagenic process of PEL. vFLIP expression in the CD19+ Bcells results in splenomegaly, with an increase in both T and B-cells, and with a relative increase of the T versus B-cell ratio. Although primary follicles were enlarged, the expression of vFLIP in the CD19+ B-cells results in lack of germinal center formation in the spleen, lymph nodes and intestine, and in partially impaired class-switching recombination. These results indicate that, by constitutively activating the NF-kB pathway in pre-germinal center B-cells expressing CD19, the normal B-cell differentiation is impaired, and provide clues about possible aberrant differentiation in PEL cells. Presenting author Email: gib2004@med.cornell.edu 37
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