Polyomaviruses cause a variety of severe human diseases particularly in immunocompromised individuals. No specific anti-viral treatments or prophylactic approaches exist to target this family of viruses. There are several critical gaps in our current knowledge of the molecular mechanism of viral replication and tumorigenesis. Our long-term goals are to identify how these viruses subvert normal host cellular processes to facilitate viral replication, and how these interactions may result in oncogenesis. Our previous studies revealed an intricate balanced relationship between viral replication and virus-induced host genomic instability. These results lead to our central hypothesis that an activated cellular DNA damage response (DDR) is important for facilitating viral replication and maintaining host genome stability during polyomavirus infection. Towards this hypothesis, we have identified host mismatch repair system and replicating viral DNA as novel factors contributing to DDR activation. We have also discovered that the ability of polyomavirus to cause host genomic DNA damage is linked to its ability to replicate viral DNA. Guided by strong preliminary data, we propose to pursue three Specific Aims to characterize DDR activation mechanism and how the DDR ties together viral replication and host genomic stability: (1) To define the role of host mismatch repair proteins in polyomavirus replication and polyomavirus-induced DDR activation. (2) To determine the viral DNA triggers that activate the DDR upon polyomavirus infection. (3) To elucidate the molecular mechanism by which polyomavirus induces host genome instability. Collectively, our proposed research will broadly impact the field by characterizing the essential roles that the DDR plays in promoting viral replication and maintaining host genome stability. These studies will have the potential to uncover novel molecular mechanisms underlying polyomavirus replication as well as viral oncogenesis. These findings may be extrapolated to other DNA viruses and to our understanding of normal cellular processes.

Public Health Relevance

Polyomaviruses are a family of viruses associated with severe human diseases and a subset of them can also cause cancers. Our proposed studies aim to understand the interactions between polyomaviruses and the host DNA damage response, a cellular pathway important for both viral replication and host genome maintenance. This research will have the potential to reveal novel therapeutic host targets to treat polyomavirus-related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI123162-02
Application #
9204729
Study Section
Virology - B Study Section (VIRB)
Program Officer
Natarajan, Ramya
Project Start
2016-01-11
Project End
2020-12-31
Budget Start
2017-01-01
Budget End
2017-12-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Imperiale, Michael J; Jiang, Mengxi (2016) Polyomavirus Persistence. Annu Rev Virol 3:517-532
Verhalen, Brandy; Starrett, Gabriel J; Harris, Reuben S et al. (2016) Functional Upregulation of the DNA Cytosine Deaminase APOBEC3B by Polyomaviruses. J Virol 90:6379-6386