Papillomaviruses (PVs) are small DNA tumor viruses that infect the epithelia of humans and animals, causing benign hyperproliferative lesions. In most cases, PV infections are cleared after several months following activation of the host immune system against viral antigen. 1 However, occasionally the lesions do not regress and can progress to cancer. Certain PVs are more commonly associated with malignancy, including the human PV (HPV) types 16 and 18, high-risk viruses for the development of cervical cancer in women, 2 and bovine PV (BPV) type 4, associated with carcinomas of the alimentary canal in cattle. 3 Persistent viral infection is required for neoplastic progression and failure of virus clearance is attributed to a poor immunologic response.The PV genome encodes 3 transforming proteins, E5, E6 and E7. E5 is a small hydrophobic protein ranging in size from 42 amino acid residues in BPV-4 to 83 amino acid residues in HPV-16. E6 and E7 are the main transforming proteins of HPV. 4,5 E5 is the major transforming protein of BPV and plays a lesser role in transformation by HPV. 6 While E6 and E7 are expressed throughout the course of the disease and are necessary for the maintenance of a transformed phenotype, E5 is expressed during the early stages of infection and its expression is often, but not always, extinguished as the lesion progresses toward malignancy. 6 These characteristics point to a role of E5 in establishment of PV infection and the initiation of cell transformation.The E5 protein is localized in the Golgi apparatus (GA), endoplasmic reticulum and occasionally the plasma membrane of the host cell. Its localization in the endomembrane compartments, where it interacts with the vacuolar ATPase 16k ductin/ subunit c, 7-9 is deemed responsible for the lack of acidification of the GA and endolysosomes and the consequent impaired functions of these organelles. 10,11 We have shown that one of the outcomes of BPV E5 expression in primary cells is the retention of major histocompatibility (MHC) class I complexes in the GA and the inhibition of their transport to the cell surface. 12,13 Furthermore, BPV E5 inhibits both transcription of the MHC class I heavy chain gene and affects the stability of the heavy chain protein. 12 In this study, we show that HPV-16 E5 also prevents the transport of MHC (HLA) class I complexes to the cell surface due to retention in the GA. Moreover, we show that HPV-16 E5 selectively downregulates HLA-A and HLA-B molecules on the cell surface but does not affect the transport of HLA-C and HLA-E. These studies identify a potential novel mechanism by which PV-infected cells may avoid clearance by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, aiding in the establishment and persistence of PV infection. Material and methods HPV-16 E5 expression constructsThe E5 ORF was cloned into 3 expression plasmids: pcDNA3 (Invitrogen, Glasgow, U.K.), under the transcriptional control of the universal cytomegalovirus (CMV) immediate early promoter (pc-16E5); pL2, under control o...

PI3K/AKT/mTOR pathway is one of the most important signaling pathways involved in normal cellular processes. Its aberrant activation modulates autophagy, epithelialmesenchymal transition, apoptosis, chemoresistance, and metastasis in many human cancers.Emerging evidence demonstrates that some infections as well as epigenetic regulatory mechanisms can control PI3K/AKT/mTOR signaling pathway. In this review, we focused on the role of this pathway in gastric cancer development, prognosis, and metastasis, with an emphasis on epigenetic alterations including DNA methylation, histone modifications, and post-transcriptional modulations through non-coding RNAs fluctuations as well as H. pylori and Epstein-Barr virus infections. Finally, we reviewed different molecular targets and therapeutic agents in clinical trials as a potential strategy for gastric cancer treatment through the PI3K/AKT/mTOR pathway.

Human papillomavirus type 16 E5 protein (HPV-16 E5) is expressed early in papillomavirus infection and is localised primarily in the cell Golgi apparatus (GA) and endoplasmic reticulum. E5 prevents transport of the major histocompatibility class I (MHC I; HLA class I in humans) to the cell surface and retains the complex in the GA. We report that these effects are due, at least in part, to the interaction between E5 and HLA I heavy chain (HC). We also demonstrate that the down-regulation of surface HLA I and interaction with HC are mediated by the first hydrophobic domain of E5. Although E5 downregulates classical HLA selectively as it does not downregulate non-classical HLA, the interaction with the HC of classical HLA I is not specific for a particular haplotype of HLA I. This suggests that E5 can interfere with antigen presentation by most, if not all, classical HLA I haplotypes, with potentially serious consequences as the ability of infected cells to present antigenic peptides to effector T cells would be compromised. ' 2006 Wiley-Liss, Inc.Key words: HPV; E5; HLA class I; heavy chain; interaction; immunomodulation Human papillomaviruses (HPVs) infect mucosal and cutaneous epithelia and induce lesions that can persist and progress to cancer. The mildest forms of HPV disease are benign hyperproliferative lesions, known as warts or papillomas. In most cases, these lesions are cleared after several months following activation of the host immune system against viral antigen.1 However, due to the ability of certain types of HPVs to avoid immune clearance, occasionally, the lesions do not regress and can progress to cancer. This is especially true for HPV type 16, which is involved in the majority of cases of HPV-induced cervical cancers.2 The ability of the virus to avoid immune clearance is due to several factors dependent on the virus life cycle, but also on active mechanisms operated by the viral proteins to counteract the host immune attack. Elimination of virally infected cells requires cytotoxic Tlymphocytes (CTL) that can recognise and kill virally infected cells via ligation of their receptor to major histocompatibility class I complex (MHC I; HLA I in humans) bound to viral peptides on the surface of infected cells. 3One of the potential effectors of HPV-16 escape from host immunosurveillance is the viral oncoprotein E5.4 E5 is a hydrophobic membrane protein 83 amino acids long, possessing 3 well-defined hydrophobic regions. E5 is expressed early in papillomavirus infection in the deep layers of the infected epithelium 5,6 (Araibi et al., unpublished results) and is localised mainly in the endoplasmic reticulum (ER) and Golgi apparatus (GA) membranes. 7 We have previously shown that HPV-16 E5 downregulates the expression of surface HLA I by retaining the complex in the GA, and this downregulation is selective, as E5 does not interfere with nonclassical MHC. This may allow the virus to establish itself by avoiding clearance of virus-infected cells by both CTL and natural killer cells. 4 Here we show tha...

HPV-16 is the major causes of cervical cancer. Persistence of infection is a necessary event for progression of the infection to cancer. Among other factors, virus persistence is due the viral proteins fighting the immune response. HPV-16 E5 down-regulates MHC/HLA class I, which is much reduced on the cell surface and accumulates in the Golgi apparatus in cells expressing E5. This effect is observed also in W12 cells, which mimic early cervical intraepithelial progression to cervical cancer. The functional effect of MHC I down-regulation on human CD8 T cells is not known, because of the need for HLA-matched, HPV-specific T cells that recognise E5 expressing-cells. Here we employ a heterologous cell/MHC I system which uses mouse cells expressing both E5 and HLA-A2, and A2-restricted CTLs; we show that the E5-induced reduction of HLA-A2 has a functional impact by reducing recognition of E5 expressing cells by HPV specific CD8+ T cells.