Chronic infections and re-infections by human cytomegalovirus (HCMV) cannot be eliminated by the host's immune system despite an extraordinary strong T cell response. Viral stealth strategies preventing the activation of immune cells and the recognition of virally infected cells are thought to be essential to escape immune eradication. Inhibiting the presentation of viral antigens by major histocompatibility complex (MHC) molecules is thought to play a key role in cytomegaloviral immune escape. However, the role of inhibiting MHC presentation for HCMV pathogenesis and persistence has not been established since infections by cytomegaloviruses are highly host-restricted and HCMV does not infect immunocompetent animals. Besides chimpanzee CMV, which is not a feasible animal model, the closest relative of HCMV is Rhesus CMV (RhCMV) which infects non-human primates. Similar to HCMV, we observed that RhCMV is capable of re-infecting seropositive animals and establishing a persistent infection. Using this new model, we will test the hypothesis that preventing expression of MHC I is essential for the establishment and maintenance of persistent infection in immunocompetent hosts. We show that RhCMV encodes inhibitors of MHC assembly that are functional and sequence homologues of the HCMV US6-family of glycoproteins US2, US3, US6 and US11. We further demonstrate RhCMV encodes additional modulator(s) of MHC I expression within a 3kb genomic fragment, Rh175-180 that encodes RhCMV-specific genes but also overlaps with the transcript of Rh181, the RhCMV homologue of HCMV US1. This novel mechanism, termed viral interference with heavy chain expression (VIHCE), acts post-transcriptionally but prior to completion of heavy chain synthesis. Thus, VIHCE precedes inhibition of MHC I assembly and transport by US6-related proteins. The goals of this proposal are i) to identify which of the gene products encoded in the Rh175-181 region are responsible for VIHCE, ii) to characterize the molecular mechanism of VIHCE, and iii) to determine the role of preventing MHC I expression, assembly or transport for escaping immune detection by CD8+ lymphocytes during establishment and maintenance of persistent infection of immunocompetent animals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI059457-04
Application #
7390725
Study Section
Virology - B Study Section (VIRB)
Program Officer
Beisel, Christopher E
Project Start
2005-07-01
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
4
Fiscal Year
2008
Total Cost
$361,765
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
Child, Stephanie J; Hickson, Sarah E; Bayer, Avraham et al. (2018) Antagonism of the Protein Kinase R Pathway in Human Cells by Rhesus Cytomegalovirus. J Virol 92:
Früh, Klaus; Picker, Louis (2017) CD8+ T cell programming by cytomegalovirus vectors: applications in prophylactic and therapeutic vaccination. Curr Opin Immunol 47:52-56
Hansen, Scott G; Wu, Helen L; Burwitz, Benjamin J et al. (2016) Broadly targeted CD8? T cell responses restricted by major histocompatibility complex E. Science 351:714-20
Sturgill, Elizabeth R; Malouli, Daniel; Hansen, Scott G et al. (2016) Natural Killer Cell Evasion Is Essential for Infection by Rhesus Cytomegalovirus. PLoS Pathog 12:e1005868
Malouli, Daniel; Hansen, Scott G; Nakayasu, Ernesto S et al. (2014) Cytomegalovirus pp65 limits dissemination but is dispensable for persistence. J Clin Invest 124:1928-44
Hansen, Scott G; Sacha, Jonah B; Hughes, Colette M et al. (2013) Cytomegalovirus vectors violate CD8+ T cell epitope recognition paradigms. Science 340:1237874
Malouli, Daniel; Nakayasu, Ernesto S; Viswanathan, Kasinath et al. (2012) Reevaluation of the coding potential and proteomic analysis of the BAC-derived rhesus cytomegalovirus strain 68-1. J Virol 86:8959-73
Viswanathan, Kasinath; Smith, M Shane; Malouli, Daniel et al. (2011) BST2/Tetherin enhances entry of human cytomegalovirus. PLoS Pathog 7:e1002332
Richards, Rebecca; Scholz, Isabel; Powers, Colin et al. (2011) The cytoplasmic domain of rhesus cytomegalovirus Rh178 interrupts translation of major histocompatibility class I leader peptide-containing proteins prior to translocation. J Virol 85:8766-76
DeFilippis, Victor R; Alvarado, David; Sali, Tina et al. (2010) Human cytomegalovirus induces the interferon response via the DNA sensor ZBP1. J Virol 84:585-98

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