Kaposi's sarcoma-associated herpes virus (KSHV), an important human pathogen accounting for a Large percentage of virally-caused cancers worldwide, has evolved a variety of stratagems for evading host immune responses to establish a life-long persistent infection and for deregulating cell growth control to achieve oncogenesis. The goal of Project 1 is to better understand how the KSHV evades host's innate and adaptive immune controls and subsequently deregulates host's growth controls, with a specific focus on the KSHV K3 and K5 genes. Our preliminary study has shown (1) that both the K3 and K5 membrane E3 ubiquitin ligase proteins downregulate MHC class I and CDId molecules, and the K5 downregulates numerous immune modulatory proteins (interferon gamma receptor 1, B7-2, ICAM-1, tetherin etc.). We have also discovered (2) that the K3 or K5 expression apparently increases cell proliferation and induced tumorigenicity in nude mice, and (3) that the K5 gene whose promoter carries an active epigenetic mark during latency is readily expressed in Kaposi's Sarcoma tumors, as well as in Primary Effusion Lymphomas and multicastleman's diseases. (4) Furthermore, we have developed an "infectious" KSHV bacterial artificial chromosome (BAC16) to facilitate the efficient genetic manipulation ofthe viral genome. A main hypothesis of Project 1 is that the KSHV has evolved to carry the K3 and K5 genes with similar, yet distinct biochemical activities to ensure comprehensive protection from host immune effectors and to deregulate cell growth control. Despite previous extensive cell biology and biochemical studies, the detailed in vivo biological evidences of K3- and K5-mediated immune evasion in viral persistence and pathogenesis are still elusive. In this proposal, we will attempt to define in vivo roles ofthe K3 and K5 in vial persistence and oncogenesis. Specifically, we will test whether the loss of K3 and/or K5 genes from the KSHV genome affects the establishment of viral persistence in NOD/SCID IL2Ry-/- "humanized" mice and the induction of viral oncogenic transformation of primary embryonic mesenchymal stem cells (MSC) in cultures and nude mice. This proposal is highly innovative and its successful outcome should significantly impact our understanding of KSHV biology.

Public Health Relevance

Host immune responses play essential roles in the suppression of viral infection/replication and the elimination of viruses from infected hosts. To avoid these host innate and adaptive immune responses, herpes viruses have evolved elaborate mechanisms to target and modulate differing aspects of the host's immune systems, which ultimately lead to persistent infection and pathogenesis. Thus, understanding KSHV-mediated immune evasion tricks and pathogenesis tactics is the primary goal of this application.

National Institute of Health (NIH)
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University of Southern California
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Rodgers, Mary A; Bowman, James W; Fujita, Hiroaki et al. (2014) The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation. J Exp Med 211:1333-47
Yan, Qin; Ma, Xinting; Shen, Chenyou et al. (2014) Inhibition of Kaposi's sarcoma-associated herpesvirus lytic replication by HIV-1 Nef and cellular microRNA hsa-miR-1258. J Virol 88:4987-5000
Brulois, Kevin; Toth, Zsolt; Wong, Lai-Yee et al. (2014) Kaposi's sarcoma-associated herpesvirus K3 and K5 ubiquitin E3 ligases have stage-specific immune evasion roles during lytic replication. J Virol 88:9335-49
Shi, Mude; Cho, Hyelim; Inn, Kyung-Soo et al. (2014) Negative regulation of NF-?B activity by brain-specific TRIpartite Motif protein 9. Nat Commun 5:4820
Zhu, Ying; Huang, Yufei; Jung, Jae U et al. (2014) Viral miRNA targeting of bicistronic and polycistronic transcripts. Curr Opin Virol 7:66-72
Brulois, Kevin; Jung, Jae U (2014) Interplay between Kaposi's sarcoma-associated herpesvirus and the innate immune system. Cytokine Growth Factor Rev 25:597-609
Jones, Tiffany; Ramos da Silva, Suzane; Bedolla, Roble et al. (2014) Viral cyclin promotes KSHV-induced cellular transformation and tumorigenesis by overriding contact inhibition. Cell Cycle 13:845-58
Lee, Myung-Shin; Jones, Tiffany; Song, Dae-Yong et al. (2014) Exploitation of the complement system by oncogenic Kaposi's sarcoma-associated herpesvirus for cell survival and persistent infection. PLoS Pathog 10:e1004412
Full, Florian; Jungnickl, Doris; Reuter, Nina et al. (2014) Kaposi's sarcoma associated herpesvirus tegument protein ORF75 is essential for viral lytic replication and plays a critical role in the antagonization of ND10-instituted intrinsic immunity. PLoS Pathog 10:e1003863
Liang, Qiming; Seo, Gil Ju; Choi, Youn Jung et al. (2014) Crosstalk between the cGAS DNA sensor and Beclin-1 autophagy protein shapes innate antimicrobial immune responses. Cell Host Microbe 15:228-38

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