Date

June 2008

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Molecular Microbiology and Immunology

Institution

Oregon Health & Science University

Abstract

Viruses are obligate intracellular parasites that cause a wide range of disease in all forms of life. In order to protect the host organism from the damaging effects of virus infection, the immune system has evolved a wide array of mechanisms that aim to prevent viruses ability to replicate. Consequently, viruses have developed countermeasures against the immune system. In many cases, this cat and mouse game has progressed over millions of years as viruses co-evolved with their hosts, making the virus extremely well adapted to its particular replicative environment. Cytomegaloviruses (CMVs) are a fine example of this co-evolution, where each mammalian species has its own specific CMV that is unable to replicate in other species. As a result, each CMV can contain immune evasion mechanisms both conserved with other CMVs infecting animals of near evolutionary ancestry, and unique immune evasion mechanisms that have evolved after an evolutionary split of two animal species. In this dissertation, we document the discovery of a unique immunomodulatory protein encoded by Rhesus CMV that we have termed viral inhibitor of heavy chain expression (VIHCE). VIHCE is unique both in terms of its lack of sequence similarity to any other known protein, and in terms of the mechanism by which it acts. We show that VIHCE is able to specifically block the biosynthesis of major histocompatability complex type I heavy chains by targeting their signal peptides. Additionally, we identify a role for inhibitors of MHC-I antigen presentation during Rhesus CMV infection in vivo, showing that these immune evasion genes are necessary for CMVs surprising ability to reinfect an already seropositive host.

Identifier

doi:10.6083/M4SQ8XDS

School

School of Medicine

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