Persistent infections of human gamma-herpesviruses, Epstein-Barr virus (EBV or HHV-4) and Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8), are associated with several malignancies, which frequently develop in immunodeficiency virus (HIV)-infected AIDS patients and often found in their oral cavities. Through co-evolution with hosts, herpesviruses have acquired many strategies to counteract various aspects of the type interferon (IFN) responses, strongly indicating a powerful selective pressure from type I IFNs on the virus to antagonize it for successful infection. Type I IFNs are not only the major anti-viral effector of innate immunity but also important for the development of long-term memory adaptive responses. The overall hypothesis is that the ability to evade the type I IFN response is critical for effective viral growth in a host and that removal f the anti-IFN ability from the virus leads to a highly attenuated but immunogenic virus suitable for vaccination. To test the hypothesis, the following specific aims will be pursued: 1) to elucidate the mechanisms by which the viral genes inhibit type I IFN signaling, 2) to determine the biological significance of anti-IFN genes in vitro and in vivo, and 3) to test a rational therapeutc vaccine strategy by selective inactivation of viral immune evasion genes. The long-term goal is to develop strategies for preventing and treating cancers associated with persistent infections of KSHV and EBV. Accomplishment of the above aims, which is an important step towards achievement of the long-term goal, will demonstrate the feasibility of the therapeutic vaccine approach and establish a foundation for future pre-clinical studies in the KSHV primate model. Moreover, elucidating the anti-IFN function of a group of conserved viral proteins may reveal potential targets for therapeutic measures.

Public Health Relevance

Herpesviruses are associated with various diseases, which are especially devastating in HIV-infected individuals and AIDS patients. The knowledge obtained from this study can be applied toward the therapies for persistent herpesviral infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE023591-03
Application #
8932592
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Gannot, Gallya
Project Start
2013-09-13
Project End
2016-04-30
Budget Start
2015-05-01
Budget End
2016-04-30
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Pharmacology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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
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:
Dai, Xinghong; Li, Zhihai; Lai, Mason et al. (2017) In situ structures of the genome and genome-delivery apparatus in a single-stranded RNA virus. Nature 541:112-116
Gong, Danyang; Kim, Yong Hoon; Xiao, Yuchen et al. (2016) A Herpesvirus Protein Selectively Inhibits Cellular mRNA Nuclear Export. Cell Host Microbe 20:642-653
Wu, Nicholas C; Dai, Lei; Olson, C Anders et al. (2016) Adaptation in protein fitness landscapes is facilitated by indirect paths. Elife 5:
Dai, Xinghong; Gong, Danyang; Xiao, Yuchen et al. (2015) CryoEM and mutagenesis reveal that the smallest capsid protein cements and stabilizes Kaposi's sarcoma-associated herpesvirus capsid. Proc Natl Acad Sci U S A 112:E649-56