In vivo Interactions Between a Gamma-Herpesvirus and Innate Immune Responses

通过逃避宿主的免疫监视，疱疹病毒可以在宿主体内持续存在并引起各种疾病。因此，了解病毒免疫逃避的机制不仅对开发控制疱疹病毒疾病的疫苗方法至关重要，而且可能导致有关宿主先天防御系统的新发现。在宿主免疫系统的两翼——先天免疫和适应性免疫中，先天免疫反应是抑制疱疹病毒粘膜感染的关键，因为它们是深刻影响疱疹病毒免疫控制的第一道防线。γ -疱疹病毒亚家族的成员在淋巴细胞中建立潜伏感染并在被感染的宿主中引起良性或恶性肿瘤的能力是不同的。卡波西肉瘤相关疱疹病毒（KSHV/HHV-8）是人类感染的两种疱疹病毒之一

By evading host immune surveillance, herpesviruses can persist in hosts and cause various diseases. Thus, understanding the mechanisms of viral immune evasion is not only essential for developing vaccine approaches to control herpesviral diseases, but also may lead to novel discoveries about the host innate defense system. Of the two wings of the host immune system, innate and adaptive, innate immune responses are very critical for restraining mucosal infection of herpesvirus because they are the first line of defense that profoundly affects the immune control of herpesvirus. Members of the gamma-herpesvirus subfamily are distinct in their ability to establish latent infections in lymphocytes and cause benign or malignant tumors in infected hosts. Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) is one of two human gamma-herpesviruses and is associated with tumors, such as Kaposi's sarcoma and primary effusion lymphoma. In spite of the viruses' medical importance, the studies of human gamma-herpesvirus infection have been limited mostly to in vitro experiments because of their restricted host range. Therefore, mouse infection by murine gammaherpesvirus68 (MHV-68), which is biologically and genetically related to KSHV-HHV-8, has been used as a small animal model for exploring host-virus interactions during gamma-herpesvirus infection. A MHV-68 ORF expression library was screened, which reveal that three non-essential genes conserved among gamma-herpesviruses, block signaling induced by type I interferons (IFN). Interestingly, all three ORFs share a conserved dUTPase-related domain (DURO), although only one of them possesses enzymatic activity. We propose to characterize these three viral dUTPase-related proteins (DURPs) and the biological significance of their anti-IFN functions. Furthermore, a strategy of inactivating viral anti-IFN genes to generate a live-attenuated virus was explored as a new strategy for vaccination. The proposed research will assess the function of a group of conserved viral proteins, demonstrate the feasibility of the vaccine approach and establish a foundation for future clinical application. Taking a similar approach, this Project 4 will use MHV-68 infection of mice as a model system to assess the biological relevance of the other viral immune evasion genes and virus-host interactions that have been identified in Project 1, 2 and 3, and evaluate their potential utilities in vaccine development.