The Human Papillomavirus E7 Protein Is Able to Inhibit the Antiviral and Anti-growth Functions of Interferon-α

Barnard, Paula; Payne, Elizabeth; McMillan, Nigel A.J.

doi:10.1006/viro.2000.0584

Cited by 117 publications

(78 citation statements)

References 24 publications

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“…Several in vitro studies demonstrated the ability of HPV oncoproteins to control signalling pathways that lead to the expression of IFNs and IFN-inducible genes (Barnard et al, 2000;Koromilas et al, 2001;O'Brien & Saveria Campo, 2002). Expression of HPV16 E6 in human keratinocytes was able to diminish the induction of IFN-b gene expression by Sendai virus and, consequently, the expression of IFN-inducible genes (Ronco et al, 1998).…”

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confidence: 99%

Altered expression of UVB-induced cytokines in human papillomavirus-immortalized epithelial cells

Dell’Oste

Azzimonti

Mondini

et al. 2008

Journal of General Virology

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Keratinocytes can be induced to produce cytokines by exogenous stimuli, such as UVB, and dysregulation of this production has been described in various skin diseases, including cancer. In this study, we compared the effect of UVB on the secretion of several cytokines involved in inflammation by human keratinocytes immortalized or not with human papillomavirus (HPV)16 or HPV38 at the mRNA and protein levels. We show that expression of the HPV E6/E7 oncoproteins influences not only the basal cytokine secretion profile of keratinocytes, but also its modulation upon UVB irradiation. In particular, UVB upregulates interleukin (IL)-6, IL-8 and transforming growth factor (TGF)-b in HPV-immortalized cells to a higher extent than in control keratinocytes. Moreover, expression of other pro-inflammatory molecules such as S100A8/9 and interferon (IFN)-k was downregulated in HPV-immortalized cells. These data support the functional similarity between HPV16 and 38, and suggest an active role of these viruses in modulation of the inflammatory process.The association of chronic inflammation with the development of several forms of cancer is a well-accepted notion and has been the focus of several experimental tumour systems (Mueller, 2006). Persistent expression of proinflammatory cytokines at tumour sites may exert both protective and detrimental effects, ranging from an increase in malignant cell invasiveness to promotion of an antitumour immune surveillance that may counteract malignant cell growth (de Visser et al., 2006).Keratinocytes can be induced to produce cytokines by several exogenous stimuli and dysregulation of this production has been described in several skin diseases, including cancer (van Kempen et al., 2003). One of the main exogenous inducers seems to be UVB irradiation. It stimulates keratinocyte cultures to secrete pro-inflammatory cytokines such as tumour necrosis factor-a (TNF-a), interleukin-1b (IL-1b), IL-6, IL-10 and IL-8. The release of these cytokines can trigger a cutaneous inflammatory response that develops in skin exposed to sunlight and sunburn (Kupper et al., 1987;Kondo et al., 1993;Strickland et al., 1997). The preferential localization of skin squamous cell carcinoma (SCC) and human papillomavirus (HPV) infection to chronically sun-exposed body sites strongly suggests that UV and HPV may synergistically cooperate in the development of skin lesions (Pfister 2003; Akgül et al., 2006). One possibility is that this synergism may partly act at the level of the skin inflammatory response, but the effects of UVB irradiation on cytokine production by HPV-infected cells has not been studied yet (Ruhland & De Villiers, 2001).The differential expression profile of pro-inflammatory molecules comparing the conditions of mucosal (alpha genus) and cutaneous (beta genus) HPV genotypes (de Villiers et al., 2004) has been reported (Woodworth & Simpson, 1993;Smola-Hess et al., 2001;De Andrea et al., 2007), but much less is known about the synergistic effect of A supplementary figure is available with the onli...

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confidence: 99%

Altered expression of UVB-induced cytokines in human papillomavirus-immortalized epithelial cells

Dell’Oste

Azzimonti

Mondini

et al. 2008

Journal of General Virology

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“…For example, expression of HPV E6 and E7 protein prevents the immunoregulatory effects of IFN-a-and IFN-b-mediated antiviral responses. 20 It is furthermore observed that women with cervical cancer develop poor levels of E7-specific CTLs in response to the developing tumor 5,6 or to an E7 vaccine. 21 This poor cellular immune response may be caused by the expression of E7 in epithelial cells lacking costimulation, which may lead not only to immunosuppression but also to immunological tolerance.…”

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confidence: 99%

Induction of human papilloma virus E6/E7-specific cytotoxic T-lymphocyte activity in immune-tolerant, E6/E7-transgenic mice

Riezebos‐Brilman

Regts

et al. 2005

Gene Ther

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Despite promising preclinical results of various therapeutic anticancer immunization strategies, these approaches may not be effective enough to eradicate tumors in cancer patients. While most animal models are based on fastgrowing transplantable tumors, malignancies in, for example, cervical cancer patients in general develop much more slowly, which may lead to immune suppression and/or immune tolerance. As a consequence, the immunomodulating signal of any therapeutic immunization regimen should be sufficiently potent to overcome this immunocompromised condition. In previous studies, we demonstrated that an experimental vaccine against human papillomavirus (HPV)-induced cervical cancer, based on Semliki Forest virus (SFV), induces robust HPV-specific cellular immune responses in mice. Now we studied whether this strategy is potent enough to also prime a cellular immune response in immune-tolerant HPV transgenic mice, in which CTL activity cannot be induced using protein or DNA vaccines. We demonstrate that, depending on the route of immunization, SFV-expressing HPV16 E6 and E7 indeed has the capacity to induce HPV16 E7-specific cytotoxic T cells in HPVtransgenic mice. Gene Therapy (2005) Cervical cancer is the third most common cancer among women worldwide. It is caused by infection with highrisk human papillomavirus (HPV), in particular types 16, 18, 31, 33 or 45. Indeed, in over 99% of all cervical carcinomas, DNA derived from these HPV types is detectable. 1 High-risk HPVs have the capacity to transform cervical epithelial cells by integrating the open reading frames encoding the viral early proteins E6 and E7 into the host cell genome. This integration may lead to constitutive overexpression of E6 and E7, mediating transformation of the cells to a malignant phenotype. 2 Since the continued production of E6 and E7 is required for the maintenance of the transformed phenotype, E6 and E7 in fact represent tumor-specific antigens in cervical carcinoma and premalignant HPV-transformed cells. As a consequence, E6 and E7 are potential targets for immunotherapeutic intervention strategies involving induction or stimulation of cytotoxic T lymphocyte (CTL) activity against HPV-transformed cells. 3

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“…Both E6 and E7 oncoproteins inhibit IL-18-induced IFN-in natural killer (NK) cells [63]. Additionally the E7 oncoprotein arrests the antiviral signaling mediated by interferon-alpha (IFN-) [64,65] and has also been observed to inhibit the IRF-1-mediated activation of the IFN-promoter [66].…”

Section: Humoral Immune Responses and Cell-mediated Immune Responses mentioning

confidence: 99%

Advances in Peptide-based Human Papillomavirus Therapeutic Vaccines

Liu¹,

Hussein²,

Tóth³

et al. 2012

CTMC

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Cervical cancer is the second leading cause of cancer in women worldwide. Human papillomavirus (HPV) is responsible for all cases of cervical cancer. Commercial prophylactic HPV vaccines are now available, but unfortunately these vaccines have no therapeutic effect against established HPV infections. In order to accelerate the control of cervical cancer and treat established HPV infections, it is necessary to develop therapeutic vaccines to eradicate HPV by generating cell-mediated immunity against HPV infected cells. Two HPV-encoded early proteins, the E6 and E7 oncoproteins, are the preferred targets because they are consistently expressed in virtually all cervical cancer cells and are necessary for the induction and maintenance of HPV-associated disease. A variety of vaccine strategies have been employed targeting immune responses to these proteins. Peptide-based vaccines are a promising strategy for the development of therapeutic HPV vaccines because of their safety, stability, and ease of production. This review summarizes the prospects of peptidebased vaccines for the treatment of established HPV infections. We address the challenges that scientists currently face for developing peptide-based vaccines and explore feasible strategies for improving the potency of the induced immune response with the aim of treating established HPV infections.

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The Human Papillomavirus E7 Protein Is Able to Inhibit the Antiviral and Anti-growth Functions of Interferon-α

Cited by 117 publications

References 24 publications

Altered expression of UVB-induced cytokines in human papillomavirus-immortalized epithelial cells

Altered expression of UVB-induced cytokines in human papillomavirus-immortalized epithelial cells

Induction of human papilloma virus E6/E7-specific cytotoxic T-lymphocyte activity in immune-tolerant, E6/E7-transgenic mice

Advances in Peptide-based Human Papillomavirus Therapeutic Vaccines

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