Immune Evasion and Protein Trafficking Piracy by KSHV

Harvard University (Medical School), Boston MA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Kaposi's sarcoma-associated herpesvirus (KSHV) is the most recently described oncogenic, human herpesvirus. It is classified as a gamma-herpesvirus based on genome co-linearity and homology with several other members of this sub-group including Herpesvirus saimiri and Rhesus rhadinovirus. First identified through an association with the leading form of cancer striking HIV-infected individuals, it is now recognized that it is also the etiological agent of one of the leading causes of cancer deaths in Africa. [unreadable] [unreadable] A hallmark of the herpesviruses are their ability to persist within the host despite the presence of strong antiviral responses. In order to accomplish this feat, these viruses have evolved a number of stratagies to harness, alter and avoid the immune responses. One common stratagy is the removal of MHC class I from the surface of infected cells. Without MHC class I molecules on their surface, cells are unable to signal their infected status to immune effector cells and trigger strong, specific antiviral responses. KSHV accomplishes the removal of MHC class I from infected cells by the expression of two related gene products, K3 and K5. Additionally, the K5 protein removes at least two other molecules from the surface of cells, B7-2 and ICAM, which are critical in the regulation of components of both the innate and adaptive immune responses. Thus, KSHV has developed a single stratagy theoretically capable of pan-immune escape. A better understanding of the molecular mechanisms by which K3 and K5 control the host immune response is critical for the design of anti-viral theraputics against not only KSHV, but other herpesviruses. [unreadable] [unreadable] The goals of this project are to: (1) Utilize biochemical and microscopic techniques to define specific cellular partners of K3 and K5, which have been co-opted by KSHV to downregulate the various cell surface targets, and (2) delineate the importance of K3 and K5 to in vivo viral persistence and pathogenicity through the use of a non-human primate herpesvirus model and specific herpesvirus saimiri recombinants. [unreadable] [unreadable] These studies will facilitate a better understanding, not only of the importance of this immune evasion strategy employed by KSHV, but also of the relative importance of innate and adaptive anti-viral immune responses in controlling herpesvirus persistence. In addition, characterization of the K5-binding partners should provide insights into the cellular biology underlying protein trafficking within the cell. [unreadable] [unreadable]