Diverse Herpes Viruses Share Ability To Suppress Immune Response

Christopher S. Sullivan, Ph.D. Associate Professor Dept. Molecular Biosciences The University of Texas at Austin anMedicalResearch.com Interview with:
Christopher S. Sullivan, Ph.D.
Associate Professor
Dept. Molecular Biosciences
The University of Texas at Austin and
Jennifer Cox, lead author Graduate student in Dr. Sullivan’s laboratory.
Jennifer Cox
, lead author
Graduate student in Dr. Sullivan’s laboratory.

Jennifer Cox’s Replies:

MedicalResearch: What is the background for this study? What are the main findings?

Jennifer Cox: In the last decade, researchers have identified that many viruses encode small regulatory molecules known as microRNAs. Some viral microRNAs are able to manipulate host processes including stress responses, proliferation, and cell death. However, there are many viral microRNAs with unknown functions. Many of the viruses that encode microRNAs are associated with severe pathologies including various cancers so understanding the role of viral microRNAs can shed light on virus biology.

For this study, we focused on identifying viral microRNAs that can regulate innate immune signaling for several reasons. First, all viruses have proteins to combat interferon signaling. Second, we have identified microRNAs from two diverse viruses (retro and annello) that can inhibit interferon signaling so we hypothesized that additional viral microRNAs will perform this same function. We screened ~70 viral microRNAs for the ability to regulate innate immune signaling and identified three herpesviruses, Epstein-Barr Virus, Kaposi’s Sarcoma Associated Virus, and Human Cytomegalovirus, that inhibit the interferon response.

Epstein-Barr Virus, causes an estimated 200,000 cancers every year, including lymphomas, nasopharyngeal cancers and some stomach cancers. Interestingly, most of these cancers harbor latent EBV – a state of limited gene expression that produces no virus. microRNAs are one of the few viral gene product expressed during latency.

Our further work identified that Epstein-Barr Virus, KSHV, and Human Cytomegalovirus have converged to inhibit interferon signaling in the same manner – through decreasing expression of a central hub of innate immune signaling, CREB binding protein (CBP). We show that this regulation conveys partial resistance to the negative effects of interferon treatment on an EBV+ lymphoma cell line. Additionally, removing the microRNA from a similar cell line increases the sensitivity to interferon.

Interferon can be used in combination with other chemotherapies to treat lymphomas but varies in success. Our results may partially explain the variability seen in patients with EBV-associated cancers.

MedicalResearch: What should clinicians and patients take away from your report?

Jennifer Cox: Our report has identified that diverse herpes viruses use a shared mechanism to inhibit innate immune signaling. Our data suggests that cells with certain microRNAs are resistant to the deleterious effects of interferon treatment, a common chemotherapeutic agent.

MedicalResearch: What recommendations do you have for future research as a result of this study?

Jennifer Cox: CBP is involved in the activation of many cellular stress pathways. It would be interesting to study if the herpes viral microRNAs can inhibit additional signaling pathways. Also, a meta-analysis on tumors resistant to interferon therapy could provide further evidence that EBV microRNAs contribute to the variability seen in success of the therapy.

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Dr. Christopher Sullivan’s Replies:

MedicalResearch: What is the background for this study? What are the main findings?

Dr. Christopher Sullivan: microRNAs are small RNAs that regulate gene expression and have been the subject much excitement for their biological activities and potential clinical applications. We, and others, have shown that several different classes of viruses that undergo long-term persistent infections encode their own microRNAs. In this study, we add herpesviruses, the etiological agents of severe human disease (including cancers), to the growing list of viruses that make microRNAs that can block a particular host antiviral defense called interferon. We find a striking convergence from different types of herpesviral human pathogens, each using unrelated microRNAs to combat the interferon response. We think that this is important to understanding the natural biology of latent infection since such different types of herpesviruses appear to target the same host protein with similar biological outcomes. Our work also may help to explain previous studies that have shown some Epstein Barr Virus (EBV)-associated tumors are susceptible to interferon therapy while others are resistant.

MedicalResearch: What should clinicians and patients take away from your report?

Dr. Christopher Sullivan: Although still in the early days, our work adds to literature supporting the likelihood of microRNA-based inhibitory or enhancing drugs becoming useful drugs. In particular, our work suggests that combining new microRNA-based therapies with older approaches, in this case, interferon, may increase the effectiveness of microRNA-based therapies.

MedicalResearch: What recommendations do you have for future research as a result of this study?

Dr. Christopher Sullivan: We think it is imperative to carefully profile the microRNA repertoire of numerous EBV tumors, including the full spectrum of different cancers associated with this virus. This information combined with upcoming microRNA-based drug strategies may be an additional tool useful in rendering viral-associated tumors susceptible to the host immune response.

Citation:

Pan-viral-microRNA screening identifies interferon inhibition as a common function of diverse viruses

Jennifer E. Cox, Lydia V. McClure, Andrei Goga, and Christopher S. Sullivan
PNAS 2015 ; published ahead of print January 26, 2015, doi:10.1073/pnas.1417891112

 
ResearchBlogging.org

MedicalResearch.com Interview with:, Christopher S. Sullivan, Ph.D., Associate Professor, Dept. Molecular Biosciences, The University of Texas at Austin and, Jennifer Cox, lead author Graduate student in Dr. Sullivan’s laboratory., Jennifer Cox, lead author, & Graduate student in Dr. Sullivan’s lab. (2015). Diverse Herpes Viruses Share Ability To Suppress Immune Response MedicalResearch.com

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