Date of Award
Doctor of Philosophy (PhD)
Medical Sciences (Molecular Virology and Immunology Program)
David C. Johnson
Herpes simplex virus (HSV) is unusual in its ability to cause recurrent infection in a host with an ostensibly competent immune system. This thesis describes two mechanisms by which HSV evades the cellular immune response, which contribute to its ability to persist.
Human cells infected with HSV inhibit lysis by natural killer (NK) and lymphokine-activated killer (LAK) cells. Contrary to the conclusions of previous workers, this effect is due to infection of the lytic effector cells, as shown by experiments with mutant HSV and by immunofluorescence staining of effector cells in contact with HSV-infected targets. The inhibition of lytic effector cells by HSV by cell-to-cell spread may play an important role late in the infectious cycle.
Early in the infectious cycle, infectious virus is not present and the above mechanism cannot take effect. Instead, HSV imposes a block on the cellular pathway which presents antigen to CD8⁺ cytotoxic T lymphocytes. The result is that HSV-infected human fibroblasts show abnormalities of their class I major histocompatibility complex (MHC class I) similar to those seen in antigenpresenting mutant cell lines: the MHC class I is retained within the ER and is misfolded and unstable, implying that peptide is not associated with the heavy chain/β₂-microglobulin complex. Experiments with mutant and recombinant viruses established that this effect is due to an HSV irnmediate-early protein, ICP47, and showed that cells expressing ICP47 are not efficiently recognized and lysed by CD8+ CTL. Since ICP47 is not detectably membrane-associated, it presumably affects some cytoplasmic component of the antigen-processing pathway. One candidate for this cellular target is a small (8.5 - 9 kDa) protein, which, like ICP47, is located within the cytoplasm and nucleus of certain cell types. This protein was detected by its ability to bind to a protein consisting of ICP47 fused to the carboxy terminus of glutathione S-transferase (GST).
York, Ian A., "EVASION OF THE HUMAN CELLULAR IMMUNE RESPONSE BY HERPES SIMPLEX VIRUS" (1994). Open Access Dissertations and Theses. Paper 4049.