This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Monkeypoxvirus (MPV) is the most virulent human orthopoxvirus infection since the eradication of smallpox, which led to the classification of MPV as a category A virus. The longterm goal of this study is to understand the role of viral immune modulators for MPV virulence and to develop novel treatments and improved vaccine strategies against this emerging pathogen. In 2003, the first MPV outbreak occurred in the US due to MPV imported by pets. Although individuals infected with MPV during this outbreak developed a strong MPV-specific T cell response, we observed that MPV-specific T cells were not stimulated by MPV-infected antigen presenting cells (APC) in vitro. In contrast, infection of APC by the vaccine strain Vaccinia-virus (VV) WR activated cross-reactive CD8+ and CD4+ T cells from MPV-infected individuals. These data strongly suggest that MPV prevents T cell stimulation by expressing immunomodulators that are absent in VV. We recently reported that cowpoxvirus (CPV), which also causes zoonotic infections of humans, similarly prevented the stimulation of CPV-specific CD8+ T cells obtained from experimentally CPV-infected mice. In both CPV and MPV, we observed that CD8+ T cell escape correlates with an inhibition of the maturation of major histocompatibility complex (MHC) class I molecules. Thus, we hypothesize that by inhibiting the presentation of virus-derived peptides to T cells, both MPV and CPV render infected cells invisible to orthopoxvirus-specific CD8+ T cells. In this application we will test this hypothesis by a) determining the molecular mechanism by which MPV downregulates MHC class I molecules, b) identifying the viral inhibitor of antigen presentation (VIPR) of MPV, c) generating VIPR-deleted MPV and examining whether this recombinant virus activates MPV- specific T cells from MPV-infected humans and non-human primates (NHP). Upon completion of this exploratory project we plan to address the role of this immune modulatory mechanism for pathogenesis of MPV in NHP and for the ability of MPV to escape vaccine-induced cellular immunity.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Primate Research Center Grants (P51)
Project #
5P51RR000163-49
Application #
7716007
Study Section
Special Emphasis Panel (ZRR1-CM-8 (01))
Project Start
2008-05-01
Project End
2009-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
49
Fiscal Year
2008
Total Cost
$55,512
Indirect Cost
Name
Oregon Health and Science University
Department
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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