The long-term goal of this project is to develop an understanding of the cellular and molecular mechanisms of human cytomegalovirus (HCMV) persistence in the host. HCMV is a species-specific virus that establishes a persistent/latent infection in the host after primary infection. Herpesviruses achieve latency/persistence by restricting expression of viral genes, thereby reducing acute replication while maintaining the ability to reactivate at a later stage. This process especially in CMV is not well understood but is likely to involve both cellular and viral factors. The recent discovery of RNA interference and the widespread expression of microRNAs has uncovered a new layer of post-transcriptional gene regulation that was previously unknown. Studies by our own group and others have identified over 70 miRNA genes encoded by multiple DNA viruses, the majority of which have been identified within the herpesvirus family. Although relatively little is known about the function of virally encoded miRNAs their potential ability to regulate multiple transcripts and the lack of an immunogenic response make miRNAs ideal candidates for the promotion and maintenance of a persistent or latent viral gene expression profile. Furthermore, preliminary data presented in this proposal suggests a possible role for at least one of the HCMV miRNAs in restricting acute replication of the virus. Following bioinformatics studies we have successfully identified a number of viral target transcripts of the HCMV miRNA UL112-1. These targets include the uracil DNA glycosylase gene, which resides directly antisense to UL112-1 and is directly cleaved by the miRNA, and the major transactivating protein IE72, which is regulated post-trancsriptionally via a target sequence within the 3'UTR of the messenger RNA. In this proposal we will extend the characterization of HCMV UL112-1 during acute infection and during persistent infection. In addition we will identify and characterize the HCMV gene targets of the other virally encoded miRNAs and analyze their contribution to regulation of the virus during acute infection. Lastly we will examine the expression and function of the HCMV miRNAs in monocyte macrophages and persistently infected endothelial cells. Elucidating the mechanisms of miRNA regulation of HCMV gene expression will provide an important contribution to herpesviruses and miRNA field as a whole.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI021640-27
Application #
8098876
Study Section
Special Emphasis Panel (ZRG1-IDM-P (02))
Program Officer
Beisel, Christopher E
Project Start
1984-12-01
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
27
Fiscal Year
2011
Total Cost
$370,170
Indirect Cost
Name
Oregon Health and Science University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Hancock, Meaghan H; Hook, Lauren M; Mitchell, Jennifer et al. (2017) Human Cytomegalovirus MicroRNAs miR-US5-1 and miR-UL112-3p Block Proinflammatory Cytokine Production in Response to NF-?B-Activating Factors through Direct Downregulation of IKK? and IKK?. MBio 8:
Hancock, Meaghan H; Skalsky, Rebecca L (2017) Roles of Non-coding RNAs During Herpesvirus Infection. Curr Top Microbiol Immunol :
Hancock, Meaghan H; Nelson, Jay A (2017) Modulation of the NF?b Signalling Pathway by Human Cytomegalovirus. Virology (Hyderabad) 1:
Caviness, Katie; Bughio, Farah; Crawford, Lindsey B et al. (2016) Complex Interplay of the UL136 Isoforms Balances Cytomegalovirus Replication and Latency. MBio 7:e01986
Sylwester, Andrew; Nambiar, Kate Z; Caserta, Stefano et al. (2016) A new perspective of the structural complexity of HCMV-specific T-cell responses. Mech Ageing Dev 158:14-22
Landais, Igor; Pelton, Chantel; Streblow, Daniel et al. (2015) Human Cytomegalovirus miR-UL112-3p Targets TLR2 and Modulates the TLR2/IRAK1/NF?B Signaling Pathway. PLoS Pathog 11:e1004881
Crawford, Lindsey B; Streblow, Daniel N; Hakki, Morgan et al. (2015) Humanized mouse models of human cytomegalovirus infection. Curr Opin Virol 13:86-92
Hook, Lauren M; Grey, Finn; Grabski, Robert et al. (2014) Cytomegalovirus miRNAs target secretory pathway genes to facilitate formation of the virion assembly compartment and reduce cytokine secretion. Cell Host Microbe 15:363-73
Hook, Lauren M; Landais, Igor; Hancock, Meaghan H et al. (2014) Techniques for characterizing cytomegalovirus-encoded miRNAs. Methods Mol Biol 1119:239-65
Hakki, Morgan; Goldman, Devorah C; Streblow, Daniel N et al. (2014) HCMV infection of humanized mice after transplantation of G-CSF-mobilized peripheral blood stem cells from HCMV-seropositive donors. Biol Blood Marrow Transplant 20:132-5

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