Potential strategies utilised by papillomavirus to evade host immunity

Frazer, Ian H.; Thomas, Ranjeny; Zhou, Jiang; Leggatt, Graham R.; Dunn, Linda A.; McMillan, Nigel A.J.; Tindle, Robert W.; Filgueira, Luis; Manders, Peter; Barnard, Paula; Sharkey, Michael J.

doi:10.1111/j.1600-065x.1999.tb01288.x

Cited by 96 publications

(76 citation statements)

References 72 publications

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“…31 The immune system plays a decisive role in determining the clinical outcome of HPV disease, as demonstrated by the increased persistence and enhanced neoplastic progression of HPV infections in hosts with cell-mediated immune deficiencies. 32,33 However, even in immunocompetent individuals, HPVs persist for a significant period of time before activation of the host immune system.…”

Section: Discussionmentioning

confidence: 99%

E5 protein of human papillomavirus type 16 selectively downregulates surface HLA class I

Ashrafi

Haghshenas

Marchetti

et al. 2004

Intl Journal of Cancer

186

180

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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...

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Section: Discussionmentioning

confidence: 99%

E5 protein of human papillomavirus type 16 selectively downregulates surface HLA class I

Ashrafi

Haghshenas

Marchetti

et al. 2004

Intl Journal of Cancer

186

180

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“…Selection of cytokines was based upon previous reports on their importance in HPV-associated cervical neoplasia (30,31) or their in vitro expression following DC exposure to HPV proteins (24,32). To determine the effect of HPV18 transfection on cytokine production, transfected DCs, non-transfected DCs and DCs transfected with empty vector were cultured to confluency.…”

Section: Resultsmentioning

confidence: 99%

“…Tumor necrosis factor-α (TNF-α) interleukin-6 (IL-6), transforming growth factor-β (TGF-β) and monocyte chemotactic protein-1 (MCP-1) ELISA kits were purchased from Life Technologies. The selection of cytokines for this study was based upon published data suggesting their involvement in mechanisms controlling tumor growth or regression (14,30,(36)(37)(38). Transfected and non-transfected cells (10 6 cells/well) were placed in 12-well plates and grown to confluency and activated with lipopolysaccharide (1 µg/ml; LPS; Sigma Chemical Co., St. Louis, MO, USA).…”

Section: Rt-pcr Detection Of E6 and E7 Transcriptsmentioning

confidence: 99%

Human dendritic cells transfected with a human papilloma virus-18 construct display decreased mobility and upregulated cytokine production

Khaiboullina

Morzunov

Hall

et al. 2013

International Journal of Oncology

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Abstract. The marked depletion of dendritic cells (DCs) in skin cancers, as well as preneoplastic and neoplastic cervical epithelium, suggests a central role for DCs in productive human papillomavirus (HPV) infection and cancer promotion. It has been suggested that HPV may facilitate tumor development by reducing DC density, contributing to a decrease in local immune surveillance. In this study, we have examined the response of human DCs transfected with a construct containing the HPV18 genome and their subsequent expression of papilloma virus proteins. Transfected cells expressed the L1 major capsid protein and upregulated E6 and E7 oncoprotein transcripts as detected by RT-PCR. Transfection of DCs also resulted in a significant increase in cytokine production. Finally, we observed that HPV18 transfection decreased the migratory activity of DCs. Our data indicate that HPV transfection of DCs leads to changes in migratory activity and cytokine production, which potentially can suppress or delay immune responses to viral antigens. Additionally, changes in cytokine production by HPV-transformed human fibroblasts and human cervical epithelial cells revealed that the migratory and antigen-presenting functions of DCs may be impaired by the suppressive effects of cytokines produced by HPV-infected epithelial and stromal cells.

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“…Over the last two decades, several studies have shown the use of IFN for treating cervical intraepithelial neoplasia (CIN) ( Byrne MA et al 1986;Choo YC et al 1986;Cinel A et al 1991;Di Roma E et al 2001;Dunham AM 1990;Frazer IH et al 1999;Frost L et al 1990;Grismondi GL et al 1995;Katesmark M et al 1999;Micheletti L et al 1992;Murta EF and Tavares Murta BM, 2004;Rotola A et al 1995;Schiffman MH, 1995;Sikorski M and Zrubek H, 2003). Physical methods are the ones most utilized for treating high-grade lesions.…”

Section: Lower Genital Tractmentioning

confidence: 99%

Utilization of Interferon in Gynecologic and Breast Cancer

Nomelini

Mardegan

Murta

2007

Clinical medicine. Oncology

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Abstract:The usual treatment of gynecologic cancer has been surgery, chemotherapy and radiotherapy. New therapies are being developed to improve efficacy of treatment. Interferons are inducible secretory glycoproteins that have immunomodulatory, antiviral, anti-angiogenic and anti-proliferative effects. Their potential antitumor effect has been demonstrated in many studies. Some patients obtain benefi cial effects; in other patients the treatment failure can occur. IFNs can modulate the immune response and inhibition of tumor angiogenesis. When any alteration in gene expression occurs, there is modulation of the receptors of other cytokines and enzymes that control cell function. These alterations can infl uence the differentiation, cell proliferation rate and apoptosis. The molecular mechanisms that control apoptotic cell death can be improved through cancer management using IFN in single, combination or adjuvant treatment. Malignant cells generally present defects in programmed cell death and apoptosis. Immunomodulation and angiogenesis inhibition are indirect antitumor mechanisms mediated by apoptosis. With regard to immunomodulation, IFNs can have antitumor effects through increases in cytotoxic T cells, natural killer cells and dendritic cells. Angiogenesis inhibition can result from endothelial cell apoptosis. This factor is important in inhibiting tumor genesis and forming metastases. The aim of this review is to discuss the role of Interferon in the treatment of gynecologic malignancies/breast cancer and mechanisms of action.

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Potential strategies utilised by papillomavirus to evade host immunity

Cited by 96 publications

References 72 publications

E5 protein of human papillomavirus type 16 selectively downregulates surface HLA class I

E5 protein of human papillomavirus type 16 selectively downregulates surface HLA class I

Human dendritic cells transfected with a human papilloma virus-18 construct display decreased mobility and upregulated cytokine production

Utilization of Interferon in Gynecologic and Breast Cancer

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