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The 11 th International Workshop on KSHV & Related Agents, Birmingham, UK Pathogenesis Abstract 16 DEVELOPMENT OF ANIMAL MODELS OF KSHV INFECTION AND AIDS- ASSOCIATED DISEASE BASED ON MACAQUE RHADINOVIRUSES A. Gregory Bruce 1 , Jonathan T. Ryan 1 , Courtney Gravett 1,2 , and Timothy M. Rose 1,2 , 1 Seattle Children’s Hospital Research Institute and 2 University of Washington, Seattle WA Abstract Two related viral lineages within the Rhadinovirus genus of gammaherpesviruses have been identified in macaques and other Old World non-human primates. In macaques, the prototypes of these lineages were first identified in the rhesus macaque (Macaca mulatta); retroperitoneal fibromatosis-associated herpesvirus (RFHVMm) and rhesus rhadinovirus (RRV) members of the Rhadinovirus-1 (RV1) and RV2 lineages, respectively. Each macaque species is host to a distinct pair of RV1 and RV2 rhadinoviruses, distinguishable by molecular sequence. Both RV1 and RV2 rhadinoviruses have been implicated in diseases in macaques that closely resemble cancers and proliferative diseases associated with KSHV in humans, including Kaposi sarcoma (KS), lymphoma and multicentric Castleman’s disease. Thus, the characterization of the macaque rhadinoviruses, including the development of specific reagents and assays that enable the evaluation of their biology and life cycles, is an important aspect in the development of KSHV-related macaque models of disease. We have developed protocols for experimental infection of macaques with both RV1 and RV2 macaque rhadinoviruses, and are developing reagents and analytical approaches to follow the resulting infections and host responses to infection in vivo. We will present the current status of the first small pilot study examining the experimental infection of naïve macaques with infectious rhadinoviruses from saliva of infected macaques and subsequent chemical and viral treatments to activate virus by inducing immunosuppression. These studies will provide the groundwork for establishing relevant animal models of human disease associated with KSHV. Presenting author Email: greg.bruce@seattlechildrens.org 38
The 11 th International Workshop on KSHV & Related Agents, Birmingham, UK Pathogenesis Abstract 17 β ARRESTINS REGULATE KSHV GPCR ACTIVITY AND ARE MODULATED BY CANNABINOIDS Xuefeng Zhang, Yehoshua Maor, Jerome E. Groopman Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115 USA Abstract Kaposi’s sarcoma (KS) is a frequent neoplasm among immuno-compromised patients such as those with AIDS and after organ transplantation. Among certain populations, recreational use of cannabinoids is common and medicinal use of cannabinoids is increasing as well. Cannabinoids bind to CB1 and CB2 GPCRs on the endothelial cell surface. In our previous study, we found that low doses of Δ 9 -tetrahydrocannabinol (Δ 9 - THC), the major psychoactive ingredient of marijuana, induced KSHV GPCR expression and endothelial transformation. Using immunoprecipitation and confocal microscopy, we then found that KSHV GPCR was constitutively associated with β arrestins. β arrestins are key molecules contributing to desensitization of GPCRs. We now report that knockdown of β arrestins using RNAi technology increased KSHV GPCR expression. This resulted in phosphorylation of focal adhesion kinase (FAK) and inhibition of p53 expression. Such changes in FAK and p53 may contribute to endothelial transformation by KSHV GPCR. We also found that knockdown of β arrestins significantly induced NFκB (p65) expression in KSHV-infected HMVEC. The NFκB pathway has been observed to participate in KSHV GPCR-induced transformation. Our results indicate that β arrestins may exert inhibitory effects on KSHV GPCR activity, and when KSHV-infected cells are exposed to a strong GPCR stimulus like cannabinoids, cytosolic arrestins are preferentially recruited to activated GPCRs like CB1 and CB2. This would significantly decrease association of KSHV GPCR with β arrestins, increasing activity of KSHV GPCR and enhancing KS transformation. Presenting author Email: xzhang3@bidmc.harvard.edu 39
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