Gammaherpesviruses (GHVs) establish lifelong chronic infections that place the host at risk for numerous cancers. During chronic infection, GHVs express viral gene products that stimulate host-cell proliferation and differentiation, processes thought to facilitate long-term latent persistence and contribute to tumorigenesis. However, GHVs are not acutely transforming, and cancer is rare given the high incidence of infection among adult humans, estimated at more than 90% for Epstein-Barr virus. This suggests that host cells are equipped with an intrinsic resistance to GHV-driven proliferation and cellular immortalization, but few host molecules capable of mediating this effect are known and whether these molecules functionally restrict GHV persistence and disease in vivo has not been established. Experiments described in this proposal seek to identify and confirm the in vivo relevance of host molecules with the capacity to limit GHV chronic infection and disease in three Specific Aims. Based on preliminary studies that employed murine gammaherpesvirus-68 (MHV68) infection of mice, experiments described in Specific Aim 1 test the function of host tumor suppressor protein p53, a critical molecule for preventing neoplastic disease, as an innate barrier to MHV68 latent persistence and cellular transformation. Experiments presented in Specific Aim 2 seek to define mechanisms whereby p53 limits MHV68 latent infection. Experiments in Specific Aim 3 will provide the first in vivo test of the long- standing hypothesis that latency-associated nuclear antigen, a conserved GHV disease determinant capable of inhibiting p53 functions in tissue culture, is necessary to overcome a p53-mediated restriction to enable long- term latent infection. These experiments harness the powerful mouse and MHV68 genetic systems to address a question that is fundamental to our understanding of the GHV-host dynamic. Further, we anticipate that results of this work will inform new therapeutic approaches aimed at enhancing p53 functions to limit or prevent GHV-related cancers, especially in high-risk patients such as HIV-infected individuals or solid-organ transplant recipients.

Public Health Relevance

Gammaherpesviruses (GHVs) are ubiquitous DNA tumor viruses that establish lifelong chronic infections despite stimulating robust antiviral immune responses. Chronic GHV infections place humans and other animals at risk for numerous diseases, including cancer. Defining host pathways that limit GHV persistence and disease is important, because these pathways could likely be harnessed to prevent or limit GHV-related cancers. However, host pathways that serve to intrinsically restrict GHV persistence in latent cellular reservoirs of infection are not well defined. Experiments described in this proposal will define both intrinsic host pathways that limit GHV infection and viral factors that counter these host responses. Our results will provide experimental rationale for unique strategies aimed at preventing GHV-related disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA167065-05
Application #
9438486
Study Section
Virology - B Study Section (VIRB)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2014-04-04
Project End
2019-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Salinas, Eduardo; Gupta, Arundhati; Sifford, Jeffrey M et al. (2018) Conditional mutagenesis in vivo reveals cell type- and infection stage-specific requirements for LANA in chronic MHV68 infection. PLoS Pathog 14:e1006865
Gupta, Arundhati; Oldenburg, Darby G; Salinas, Eduardo et al. (2017) Murine Gammaherpesvirus 68 Expressing Kaposi Sarcoma-Associated Herpesvirus Latency-Associated Nuclear Antigen (LANA) Reveals both Functional Conservation and Divergence in LANA Homologs. J Virol 91:
Dong, Sihan; Forrest, J Craig; Liang, Xiaozhen (2017) Murine Gammaherpesvirus 68: A Small Animal Model for Gammaherpesvirus-Associated Diseases. Adv Exp Med Biol 1018:225-236
Li, Gang; Ward, Charles; Yeasmin, Rukhsana et al. (2017) A codon-shuffling method to prevent reversion during production of replication-defective herpesvirus stocks: Implications for herpesvirus vaccines. Sci Rep 7:44404
Sifford, Jeffrey M; Stahl, James A; Salinas, Eduardo et al. (2016) Murine Gammaherpesvirus 68 LANA and SOX Homologs Counteract ATM-Driven p53 Activity during Lytic Viral Replication. J Virol 90:2571-85
Salinas, Eduardo; Byrum, Stephanie D; Moreland, Linley E et al. (2016) Identification of Viral and Host Proteins That Interact with Murine Gammaherpesvirus 68 Latency-Associated Nuclear Antigen during Lytic Replication: a Role for Hsc70 in Viral Replication. J Virol 90:1397-413
Cieniewicz, Brandon; Dong, Qiwen; Li, Gang et al. (2015) Murine Gammaherpesvirus 68 Pathogenesis Is Independent of Caspase-1 and Caspase-11 in Mice and Impairs Interleukin-1? Production upon Extrinsic Stimulation in Culture. J Virol 89:6562-74