Study on Herpesviral Suppressor of Interferon Production
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: In acquired immunodeficiency syndrome (AIDS) patients, human immunodeficiency virus (HIV) itself does not directly cause fatal diseases; rather it provides the immunological environment in which other disease causing agents can escape from the immune restriction and cause diseases. Because of their prevalence and association with a wide variety of diseases, herpesviruses are especially notorious viruses for AIDS patients. They can remain dormant inside a human host forever without difficulty because the human immune system cannot detect and eliminate dormant herpesvirus. However, when the immune system is weakened, these dormant herpesviruses become activated and can cause various opportunistic diseases, such as Burkitt’s lymphoma and Kaposi’s sarcoma, the most common tumors in AIDS patients. The dormant state of herpesvirus is not just a simple hiding from immune system. Rather, herpesviruses are actively evading immune system’s recognition. Therefore, it is important to know exactly how herpesviruses escape immune defense and hide forever inside the human. Researching on human herpesviruses is especially challenging because it is difficult to study the natural course of herpesvirus infection within the human body. To study herpesvirus in living organism, a mouse model for human herpesvirus infection was developed. Murine herpesvirus 68 (MHV-68) is a virus for mouse, which is a close relative of human gamma-herpesviruses, one of the three subfamilies of human herpesvirus causing Burkitt’s lymphoma and Kaposi’s sarcoma. MHV-68 is actively studied by researchers to understand human herpesviruses better and to develop therapies for the diseases caused by herpesvirus. In this study, we mutate nearly all MHV-68 genes to search for genes that are important for gamma-herpesvirus to escape from the immune defense system. The viable MHV-68 mutants were used to infect both normal mice and mutant mice without type I interferon, the first line of immune defense. One of the MHV-68 mutants did not survive in normal mice, but it did grow normally in the mice without type I interferon. We named this gene as SIP (suppressor of interferon production) and we are proposing to study the immune escaping function of the SIP. The long-term goal of our research is to understand the immune escaping mechanism of human herpesvirus and to apply this knowledge into therapy development of herpesviral diseases. The objective of this proposal is to understand the immune-escaping function and the role of SIP in the growth of MHV-68 in the mice. To achieve this goal, we will study the followings: 1) The interaction of SIP with a key player of type I interferon immune defense to find how SIP works, 2) the role of SIP in the growth of MHV-68 outside mice, 3) the growth of MHV-68 without SIP in the whole body of mice using our newly developed bioluminescence imaging. The newly generated MHV-68 mutants are very useful resources to understand the immune escaping phenomenon of human gamma-herpesviruses. Using these mutants, we found SIP, and now we are studying its functions. We will use more of these mutants to study viral genes that are responsible for different immune-evasion function of herpesvirus. These studies will provide new fundamentals for the basic research and more opportunities to develop new therapies for herpesviral diseases.