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dc.contributor.authorGrunhaus, Avraham
dc.identifier.citationSource: Dissertation Abstracts International, Volume: 54-09, Section: B, page: 4508.;Advisors: Marshall S. Horwitz.
dc.description.abstractThe adenovirus (Ad) early region 3 (E3) is not essential for viral replication in tissue culture but is nevertheless conserved throughout most human Ad serotypes. Protein products from the Ad E3 region have been identified that interact with some host immunoregulatory proteins in novel and interesting ways. The E3 gp19 glycoprotein, for example, down-regulates the cell surface expression of class I major histocompatibility complex (MHC) antigens by binding to the class I heavy chain in the endoplasmic reticulum and preventing its transport to the cell surface. The expression of class I MHC proteins on the cell surface is important in the recognition of infected cells by anti-viral CD8+ cytotoxic T lymphocytes (CTL). This thesis describes the development of animal models to study the effects of Ad2 gp19 expression on in vivo pathogenesis in the mouse. Initial studies were directed at characterizing the E3 region of mouse adenovirus type 1 (MAV-1), with the intent of using this virus as a model. However, sequencing of the entire MAV-1 E3 region revealed that MAV-1 has a truncated E3 region, with fewer open reading frames (ORFs) then Ad2, and does not appear to have an Ad2 gp19 homologue. As another murine model, two VV recombinants were generated by the insertion of the isolated Ad2 gp19 ORF in either an expressing or non-expressing orientation within a region of the VV genome that is not essential for VV replication in tissue culture. VV is pathogenic in mice and at the outset of our studies it was generally believed that a CD8+ CTL response was important in the pathogenesis of VV. Our VV-expressed Ad2/E3-19K glycoprotein associated with class I MHC proteins in tissue culture and was expressed in infected tissue in the mouse. However, the expression of Ad2/E3-19K did not have a significant effect on VV pathogenesis when compared to the non-expressing control. This was measured in terms of mouse mortality, viral titers in pulmonary tissue and pulmonary pathology after an intranasal infection of various inbred murine strains. Similar results were obtained after direct intracranial infections with the VV recombinants. The conclusions from these studies are that the class I MHC-restricted CD8+ CTL response to a VV infection in the mouse can be compensated for by other immune mechanisms. The insertion of the Ad2 gp 19 ORF in the VV non-essential Hind III C region did have an attenuating effect on VV pathogenesis in vivo when compared to wild type VV. However, recombinant viral titers in infected tissue reached the same levels as wild type VV titers.
dc.publisherProQuest Dissertations & Theses
dc.titleIn vivo pathogenesis studies on the effects of class I MHC down regulation by the expression of adenovirus 2 E3-19K glycoprotein

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