title: Recombinant Murine Gamma Herpesvirus 68 Carrying KSHV G Protein-Coupled Receptor Induces Angiogenic Lesions in Mice.
abstract: Human gamma herpesviruses, including Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), are capable of inducing tumors, particularly in in immune-compromised individuals. Due to the stringent host tropism, rodents are resistant to infection by human gamma herpesviruses, creating a significant barrier for the in vivo study of viral genes that contribute to tumorigenesis. The closely-related murine gamma herpesvirus 68 (γHV68) efficiently infects laboratory mouse strains and establishes robust persistent infection without causing apparent disease. Here, we report that a recombinant γHV68 carrying the KSHV G protein-coupled receptor (kGPCR) in place of its murine counterpart induces angiogenic tumors in infected mice. Although viral GPCRs are conserved in all gamma herpesviruses, kGPCR potently activated downstream signaling and induced tumor formation in nude mouse, whereas γHV68 GPCR failed to do so. Recombinant γHV68 carrying kGPCR demonstrated more robust lytic replication ex vivo than wild-type γHV68, although both viruses underwent similar acute and latent infection in vivo. Infection of immunosuppressed mice with γHV68 carrying kGPCR, but not wild-type γHV68, induced tumors in mice that exhibited angiogenic and inflammatory features shared with human Kaposi's sarcoma. Immunohistochemistry staining identified abundant latently-infected cells and a small number of cells supporting lytic replication in tumor tissue. Thus, mouse infection with a recombinant γHV68 carrying kGPCR provides a useful small animal model for tumorigenesis induced by a human gamma herpesvirus gene in the setting of a natural course of infection.
authors.affiliation: Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Junjie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Lining
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida, Gainsville, Florida, United States of America.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Feldman
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida, Gainsville, Florida, United States of America.
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Keyes
authors.affiliation: Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: College of Life Sciences, Hunan Normal University, Changsha, Hunan, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Fan
authors.affiliation: College of Life Sciences, Hunan Normal University, Changsha, Hunan, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, Hunan, China.
authors.forename: Zanxian
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing; Suzhou Institute of Systems Medicine, Suzhou, China.
authors.forename: Jiya
authors.initials: J
authors.lastname: Sun
authors.affiliation: Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing; Suzhou Institute of Systems Medicine, Suzhou, China; Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Taijiao
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Shou-Jiang
authors.initials: SJ
authors.lastname: Gao
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida, Gainsville, Florida, United States of America.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Tibbetts
authors.affiliation: Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Pinghui
authors.initials: P
authors.lastname: Feng
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006566:Herpesviridae Infections / Q000821:virology*; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000821:virology; D018144:Rhadinovirus / Q000235:genetics*; D014412:Tumor Virus Infections / Q000821:virology*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D017735:Virus Latency / Q000276:immunology / Q000502:physiology*
chemical_list: D014764:Viral Proteins; D019204:GTP-Binding Proteins