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.
The knowledge we obtain from this study can be applied toward the therapy of herpesviral diseases. Furthermore, understanding viral mechanisms that inhibit the host immune response can help us to design novel strategies for enhancing immunogenicity and efficacy of viral vaccines.
|Yau, Edwin H; Rana, Tariq M (2018) Next-Generation Sequencing of Genome-Wide CRISPR Screens. Methods Mol Biol 1712:203-216|
|Gong, Danyang; Zhang, Tian-Hao; Zhao, Dawei et al. (2018) High-Throughput Fitness Profiling of Zika Virus E Protein Reveals Different Roles for Glycosylation during Infection of Mammalian and Mosquito Cells. iScience 1:97-111|
|Jain, Prashant; Boso, Guney; Langer, Simon et al. (2018) Large-Scale Arrayed Analysis of Protein Degradation Reveals Cellular Targets for HIV-1 Vpu. Cell Rep 22:2493-2503|
|Dai, Xinghong; Gong, Danyang; Lim, Hanyoung et al. (2018) Structure and mutagenesis reveal essential capsid protein interactions for KSHV replication. Nature 553:521-525|
|Du, Yushen; Xin, Li; Shi, Yuan et al. (2018) Genome-wide identification of interferon-sensitive mutations enables influenza vaccine design. Science 359:290-296|
|Gong, Danyang; Dai, Xinghong; Xiao, Yuchen et al. (2017) Virus-Like Vesicles of Kaposi's Sarcoma-Associated Herpesvirus Activate Lytic Replication by Triggering Differentiation Signaling. J Virol 91:|
|Yau, Edwin H; Kummetha, Indrasena Reddy; Lichinchi, Gianluigi et al. (2017) Genome-Wide CRISPR Screen for Essential Cell Growth Mediators in Mutant KRAS Colorectal Cancers. Cancer Res 77:6330-6339|
|Šedý, John R; Balmert, M Olivia; Ware, Brian C et al. (2017) A herpesvirus entry mediator mutein with selective agonist action for the inhibitory receptor B and T lymphocyte attenuator. J Biol Chem 292:21060-21070|
|Du, Yushen; Chi, Xiumei; Wang, Chong et al. (2017) Quantifying perinatal transmission of Hepatitis B viral quasispecies by tag linkage deep sequencing. Sci Rep 7:10168|
|Du, Yushen; Zhang, Tian-Hao; Dai, Lei et al. (2017) Effects of Mutations on Replicative Fitness and Major Histocompatibility Complex Class I Binding Affinity Are Among the Determinants Underlying Cytotoxic-T-Lymphocyte Escape of HIV-1 Gag Epitopes. MBio 8:|
Showing the most recent 10 out of 26 publications