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Front. Microbiol. | doi: 10.3389/fmicb.2018.00788

Inhibition of Tip60 Reduces Lytic and Latent Gene Expression of Kaposi’s Sarcoma-associated Herpes Virus (KSHV) and Proliferation of KSHV-infected Tumor Cells

 Sydney Simpson1,  Guillaume Fiches1,  Maxime Jean1, Michael Dieringer1, James McGuinness1, Sinu John2,  Meir Shamay3, Prashant Desai4,  Jian Zhu1* and  Netty Santoso1
  • 1University of Rochester, United States
  • 2National Institutes of Health (NIH), United States
  • 3Bar-Ilan University, Israel
  • 4School of Medicine, Johns Hopkins University, United States

Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic virus responsible for the development of Kaposi’s sarcoma, primary effusion lymphoma (PEL), and Multicentric Castlemann’s disease in immunocompromised individuals. Despite the burden of these diseases there are few treatment options for afflicted individuals, due in part to our limited understanding of virus-host interactions. Tip60, a histone aceytltransferase (HAT) has been previously shown to interact with both the KSHV latency associated nuclear antigen protein (LANA), which is the main factor in maintaining the viral latent state, and ORF36, a viral kinase expressed in the lytic phase. We further investigated Tip60-virus interaction to ascertain Tip60’s role in the viral life cycle, and its potential as a target for future therapeutics. Through modulation of Tip60 expression in HEK293T cells harboring a plasmid containing the KSHV viral episome, Bac36, we found that Tip60 is vital for both lytic replication as well as efficient expression of latent genes. Interestingly, Tip60 small molecule inhibitors, MG149 and NU9056, similarly inhibited latent and lytic genes, and even reduced virion production in wild-type KSHV+, EBV- PEL, BCBL-1 cells. Long-term treatment with these Tip60 inhibitors selectively decreased the viability of KSHV-infected B lymphoma cells compared to uninfected cells. From this study, we conclude that Tip60 is important for KSHV infection and its associated cancer development, and Tip60 is therefore a potential target for future antiviral and anticancer therapeutics.

Keywords: KSHV, HHV-8, Kaposi’s sarcoma, primary effusion lymphoma, TIP60, MG149, NU9056

Received: 15 Dec 2017; Accepted: 06 Apr 2018.

Edited by:

Akio Adachi, Department of Microbiology, Kansai Medical University, Japan

Reviewed by:

Takayuki Murata, Fujita Health University, Japan
Zhilong Yang, Kansas State University, United States
Binhua Ling, Tulane University, United States  

Copyright: © 2018 Simpson, Fiches, Jean, Dieringer, McGuinness, John, Shamay, Desai, Zhu and Santoso. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Jian Zhu, University of Rochester, Rochester, United States, Jian_Zhu@urmc.rochester.edu