Viruses are formidable parasites that are capable of reorganizing the gene expression program of the cell they infect to their own benefit. Viral control of the cell’s gene expression apparatus can occur either during the lytic phase or during latency. Latency is a phase of viral infection whereby the virus hides in a dormant state waiting for the proper signals to reactivate the lytic phase in a distant cellular descendant, allowing virus production and spreading. Latency allows viruses to persist in their host despite host immune responses to many viral antigens (viral proteins). Sometimes, establishment of viral latency leads to cellular transformation and cancer.
Herpesviruses constitute a large and diverse family of viruses that excel at the use of latency as a way of persistence in their host. Two human herpesviruses, Epstein Barr Virus (EBV) and Kaposi’s Sarcoma Herpesvirus (KSHV), have the ability to transform the infected cell during latency. Cellular transformation caused by infection with either of these two viruses can lead to a variety of human cancers. Our lab is interested in understanding how this class of viruses modifies the host gene expression program during latency and how this modification causes cellular transformation and disease.
Our lab is currently focused on Herpesvirus saimiri (HVS), a primate herpesvirus that can cause very aggressive leukemias and lymphomas in New World monkeys. Just like EBV and KSHV, HVS expresses different classes of non-coding RNAs (ncRNAs; RNAs that do not carry information to make proteins) during latency. Use of ncRNAs during latency is particularly advantageous for the virus since ncRNAs do not elicit the host immune response that is normally triggered upon expression of viral proteins. HVS expresses seven small ncRNAs that belong to a group called Sm-class RNAs, a group of ncRNAs that is essential for the expression of genes. We discovered that the Sm-class RNAs expressed by HVS bind and manipulate a second class of cellular ncRNAs called microRNAs (miRNAs). MiRNAs are a very important group of regulatory ncRNAs that have been intensively studied in the last decade. Impairment of miRNA function in the cell can cause many different diseases including cancer. We are currently studying how viral manipulation of cellular miRNAs during latency is related to the disease process. We are also exploring the possibility that related human herpesviruses utilize a similar strategy to manipulate host gene expression through the miRNA pathway.
We have also found that just like EBV and KSHV, HVS expresses its own miRNAs in addition to Sm-class RNAs during latency. Interestingly, the virus utilizes a novel way of making its own miRNAs. We are trying to understand why this and other viruses of the same family use novel ways of making miRNAs, and how the use of alternative miRNA biogenesis pathways can contribute to the oncogenic potential of these viruses.