Our broad goals are to understand the interactions of Epstein-Barr virus (EBV) with its host cell. EBV maintains a persistent but intermittently reactivating infection in B lymphocytes and contributes to the development of lymphoid and epithelial malignancies affecting millions of humans worldwide. How EBV gene expression modulates cellular gene expression. to maintain a homeostatic balance with the host immune response is the overall focus of our proposal. A key regulator of host cell and EBV gene expression is the early lytic EBV protein SM. SM is a nuclear protein essential for EBV lytic replication that enhances mRNA stabilization, export and processing. EBV SM also regulates cell and EBV gene expression by directing alternative splicing in a highly specific manner. We have shown that SM acts to alter splicing of cellular STAT1 mRNA and change the pattern of STAT1 expression. Our observations therefore indicate that SM may modulate host innate immune responses during the reactivation and lytic replication of EBV. Understanding the key players in viral effects on alternative splicing has the potential to open up new targets for inhibiting virus replication using directed small molecules or RNAs. We have recently found that certain interferon-stimulated genes (ISGs) induced by SM inhibit EBV replication by targeting specific EBV genes. These cytoplasmic ISGs are induced during EBV reactivation, suggesting the novel hypothesis that they may detect and act on reactivating latent viruses when they produce viral nucleic acids and proteins that exit the nucleus. A major hypothesis of this application is that cells employ innate immunity molecules to combat reactivation of internal latent viruses in ways different from those used for external pathogens. This is a new paradigm for the interaction of the innate immune system with latent infections that may broadly apply to herpesviruses and other persistent pathogens. This proposal therefore has the potential to reveal basic mechanisms of action of novel effectors with antiviral activity. Understanding new points of intersection between the immune response and EBV reactivation is important for devising new treatment strategies. We therefore propose studies with the following two specific aims: 1. Determine the mechanisms by which interferon-stimulated genes (ISGs) inhibit or enhance EBV replication. 2. Define the role of alternative splicing and cellular RNA binding proteins in EBV lytic replication and gene transactivation by SM.

Public Health Relevance

Epstein-Barr virus (EBV), a common virus that infects humans, contributes to the development of lymphoma and other cancers. This proposal is to study how EBV manipulates the infected cell to avoid the immune response (host defenses) and enhance its own replication.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Virology - B Study Section (VIRB)
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Daschner, Phillip J
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University of Utah
Schools of Medicine
Salt Lake City
United States
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Church, Trenton Mel; Verma, Dinesh; Thompson, Jacob et al. (2018) Efficient Translation of Epstein-Barr Virus (EBV) DNA Polymerase Contributes to the Enhanced Lytic Replication Phenotype of M81 EBV. J Virol 92:
Swaminathan, Sankar; Schlaberg, Robert; Lewis, Julia et al. (2016) Fatal Zika Virus Infection with Secondary Nonsexual Transmission. N Engl J Med 375:1907-1909
Verma, Dinesh; Thompson, Jacob; Swaminathan, Sankar (2016) Spironolactone blocks Epstein-Barr virus production by inhibiting EBV SM protein function. Proc Natl Acad Sci U S A 113:3609-14
Thompson, Jacob; Verma, Dinesh; Li, DaJiang et al. (2016) Identification and Characterization of the Physiological Gene Targets of the Essential Lytic Replicative Epstein-Barr Virus SM Protein. J Virol 90:1206-21
Verma, Dinesh; Li, Da-Jiang; Krueger, Brian et al. (2015) Identification of the physiological gene targets of the essential lytic replicative Kaposi's sarcoma-associated herpesvirus ORF57 protein. J Virol 89:1688-702
Li, Da-Jiang; Verma, Dinesh; Mosbruger, Tim et al. (2014) CTCF and Rad21 act as host cell restriction factors for Kaposi's sarcoma-associated herpesvirus (KSHV) lytic replication by modulating viral gene transcription. PLoS Pathog 10:e1003880
Verma, Dinesh; Kim, Eun A; Swaminathan, Sankar (2013) Cell-based screening assay for antiviral compounds targeting the ability of herpesvirus posttranscriptional regulatory proteins to stabilize viral mRNAs. J Virol 87:10742-51
Li, Da-Jiang; Verma, Dinesh; Swaminathan, Sankar (2012) Binding of cellular export factor REF/Aly by Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57 protein is not required for efficient KSHV lytic replication. J Virol 86:9866-74
Verma, Dinesh; Bais, Swarna; Gaillard, Melusine et al. (2010) Epstein-Barr Virus SM protein utilizes cellular splicing factor SRp20 to mediate alternative splicing. J Virol 84:11781-9
Han, Zhao; Verma, Dinesh; Hilscher, Chelsey et al. (2009) General and target-specific RNA binding properties of Epstein-Barr virus SM posttranscriptional regulatory protein. J Virol 83:11635-44

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