Papillomaviruses infect squamous epithelial cells and cause proliferative lesions with little if any local inflammation until they undergo regression, a process that is mediated by the cellular immune system. The PV life cycle is restricted to the squamous epithelium and is closely linked to the differentiation program of the keratinocyte. Mature virus particles are produced and shed from the desquamated surface epithelial cells without causing cell death. Consequently, there may be little local or systemic presentation of PV antigens to the immune system by professional antigen presenting cells (APCs) during a viral infection. Nonetheless, viral early gene proteins are synthesized in all layers of the squamous epithelium including the basal cells, and in a normal PV infection, these early proteins do not appear to elicit an immune response. PVs like other DNA viruses such as the herpes viruses and the adenoviruses may therefore have evolved mechanisms to avoid the immune system. Regression of PV lesions does appear to be mediated by the cellular immune system. In human genital warts, regression is associated with an infiltration by CD4+ T lymphocytes and PV infected keratinocytes have been shown to express MHC class II indicating that class II presentation of antigens is likely to play at least some role in the immune response, when it occurs, to a PV infection. As part of this program project grant, we propose to examine the potential functions of specific PV genes in evading the host immune system. We will initially focus our studies on BPV because of a recent finding by our laboratory that the E6 protein encoded by this virus can bind the clatherin-associated complex (AP- l) and is recruited to the trans-Golgi network in an AP- l dependent manner. We hypothesize that BPV- l E6 could affect the biosynthesis and delivery of critical cell proteins which utilize the endocytic pathways such as the MHC class II complex. MHC class II a and b chains are synthesized in the endoplasmic reticulum (ER) where they encounter the invariant chain (Ii). The complex is subsequently exported from the ER across the Golgi apparatus and TGN and localized to endocytic compartments where the class H molecules mature. HLA-DM, which is required for the formation of mature peptide-presenting class Il molecules, and the proper targeting of HLA-DM requires a signal that may be mediated by AP- l dependent transport. Therefore, we will test in vitro as well as in vivo whether E6 may affect the antigen presentation of viral infected cells by impairing the function of HLA-DM or other components in the endocytic pathway. The work will be extended to the HPV E6 and E7 genes.
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