Abrogated NK‐cell lysis of human papillomavirus (HPV)‐16‐bearing keratinocytes in patients with pre‐cancerous and cancerous HPV‐induced anogenital lesions

Malejczyk, Jacek; Majewski, Sławomir; Jabłońska, Stefania; Rogozinski, Tomasz; Orth, Gérard

doi:10.1002/ijc.2910430206

Cited by 43 publications

(13 citation statements)

References 36 publications

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“…Our experiments show that neither synthesis nor transport to the cell surface of HLA-C/E is affected by E5 expression, leading to the conclusion that E5 selectively inhibits surface expression of HLA-A and HLA-B. NK cells of patients with HPV-induced anogenital lesions are incapable of specific killing HPV-16-infected cells, 46 although the mechanism by which this occurs is as yet unknown. Moreover, concordant with loss of MHC class I molecules that present viral peptides, there is a very low frequency of HPV-specific HLA-A-restricted CTLs in patients infected with HPV-16, an order of magnitude lower than those found in other viral infections, including influenza A and EBV.…”

Section: Discussionmentioning

confidence: 59%

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

Ashrafi

Haghshenas

Marchetti

et al. 2004

Intl Journal of Cancer

185

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: 59%

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

Ashrafi

Haghshenas

Marchetti

et al. 2004

Intl Journal of Cancer

185

180

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“…Decreased NK cell lysis of HPV-16 ϩ keratinocytes in subjects with SIL or carcinomas has been reported (82). The same group has shown that decreased recognition of HPV-16 ϩ keratinocytes is re-lated to unresponsiveness of PBMC to immunostimulatory cytokines such as IL-2 and IFN-␣ (86).…”

Section: School Of Medicine University Of California San Francisco mentioning

confidence: 95%

“…Using HLA-2.1 transgenic mice four immunogenic peptides were identified in vivo [E6 (29)(30)(31)(32)(33)(34)(35)(36)(37)(38), E7 (11)(12)(13)(14)(15)(16)(17)(18)(19)(20), E7 (82)(83)(84)(85)(86)(87)(88)(89)(90), and E7 (86-93)]. In addition, CTL induction of PBMC from humans confirmed immunogenicity, in vitro, of three of the four peptides [E7 (11)(12)(13)(14)(15)(16)(17)(18)(19)(20), E7 (82)(83)(84)(85)(86)(87)(88)(89)(90), and E7 (86-93)]. CTL to one of the...…”

Section: Adaptive Cell-mediated Immunitymentioning

confidence: 99%

Cell-Mediated Immune Response to Human Papillomavirus Infection

Scott

Nakagawa

Moscicki

2001

Clin Diagn Lab Immunol

234

217

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Acquisition of human papillomavirus (HPV) results in an infection of variable duration which may or may not be associated with clinically apparent lesions. Lesions caused by skintropic HPV types generally manifest as cutaneous warts and most often resolve over a period of months to years. On the other hand, anogenital infections are more likely to remain clinically inapparent. The development of DNA amplificationbased tests has demonstrated that anogenital infections are quite common and generally self-limited. For example, we and others have shown by PCR testing of multiple samples collected at different points in time-that 70 to 90% of sexually active adolescents and young women who develop an incident cervical HPV infection will show clearance of infection within 12 to 30 months (47,61,94). The factors influencing the natural history of these infections are not well understood. Given that persistent anogenital infection with oncogenic HPV types is associated with increased risk of neoplasia and invasive cancers (22,59,70,71,94,124) and that cervical carcinoma remains a leading cause of death among women in developing countries (129), understanding these factors is of considerable importance.Substantial effort has been directed recently at understanding the role of the host's immune response in the natural history of HPV, and in particular, anti-viral, cell-mediated immunity. Empirical evidence for the importance of cell-mediated immunity in control of HPV infection comes from an extensive body of literature documenting the increased prevalence of HPV infection and associated disease among immunosuppressed populations, including those with iatrogenic immunosuppression such as renal transplant recipients and individuals with human immunodeficiency virus (HIV) infection. Sillman and coauthors (128) reported in 1984 on 20 immunosuppressed women with various causes of immunosuppression who had lower genital neoplasia, describing evidence of associated HPV infection in all 20. Penn, in 1986, reported a 100-fold increase in cancer of the vulva and anus in renal transplant recipients (111). In the 1990s, as molecular testing for HPV infection came into its own, several reports confirmed increased incidence of HPV infection (50) and associated morbidities, including warts (77) and cervical squamous intraepithelial lesions (SIL) (104), among immunosuppressed renal transplant recipients.The most persuasive evidence for the association between cellular immune defects and HPV infection and related morbidities comes from persons with HIV infection. Such individuals show increased prevalence of anogenital HPV infection (31, 32, 60, 105-107) as well as longer periods of HPV persistence (31,40,46,90,136). In addition, infection with multiple HPV types and with oncogenic types are more common (9,31,46,78,90,107,136). Associations between markers of HIV disease status (e.g., viral load and CD4 lymphocyte count) and HPV infection have been inconsistent. Most studies have suggested that advanced disease and greater immunological ...

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“…NK cell assay. NK cell activity of preincubated PBL was tested against human K562 myelogenous leukemia target cells in a 4-hour "Cr-release assay, as described elsewhere (22). Briefly, PBL and lo4 K562 cells were mixed in wells of round-bottom multiwell plates at effector-to-target cell ratios ranging from 80: 1 to 10: 1.…”

Section: Methodsmentioning

confidence: 99%

Production of natural killer cell activity‐augmenting factor (interleukin‐6) by human epiphyseal chondrocytes

Malejczyk

Urbanski

et al. 1992

Arthritis & Rheumatism

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Objective. We sought to determine the capacity of human epiphyseal chondrocytes to modulate the cytotoxic activity of human natural killer (NK) cells by determining whether they release interleukin-6 (IL-6), a cytokine recently shown to stimulate NK cell activity.Methods. Conditioned medium from human epiphyseal chondrocyte cultures (Ch-CM) was tested for IL-6 activity using the B9 cell hybridoma assay. Its NK cell-stimulating capacity in the presence of K562 (myelogenous leukemia) cells or human chondrocytes was evaluated in a 4-hour 51Cr-release assay. Ch-CMderived ILd/NK cell-augmenting factor activity was partially purified by high-performance liquid chromatography (HPLC) gel filtration and Western blot.Results. Ch-CM contained an NK cell-augmenting factor (NKAF) which was blocked by IL-2 or IL-6 antibodies. Ch-CM did not contain detectable IL-2 activity, but it stimulated IL-2 production by human

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Abrogated NK‐cell lysis of human papillomavirus (HPV)‐16‐bearing keratinocytes in patients with pre‐cancerous and cancerous HPV‐induced anogenital lesions

Cited by 43 publications

References 36 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

Cell-Mediated Immune Response to Human Papillomavirus Infection

Production of natural killer cell activity‐augmenting factor (interleukin‐6) by human epiphyseal chondrocytes

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