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

Ashrafi, G. Hossein; Haghshenas, Mohammad Reza; Marchetti, Barbara; O’Brien, Philippa M.; Campo, M. Saveria

doi:10.1002/ijc.20558

Cited by 189 publications

(203 citation statements)

References 51 publications

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“…31 It has been shown that HPV 16 E5 has the ability to selectively retain HLA class I A and B complexes in the golgi apparatus, preventing peptide presentation to CTLs. 32 This is consistent with our observation that the variation in class I genes may not determine the efficiency of the immune response. Rather, the observed associations imply that HLA class II antigens act indirectly on the CTL response by activation of T-helper cells.…”

Section: Discussionsupporting

confidence: 92%

HLA class II allele control of HPV load in carcinoma in situ of the cervix uteri

Beskow

Moberg

Gyllensten

2005

Intl Journal of Cancer

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Human papillomavirus (HPV) infection is the most important risk factor for development of cervical carcinoma. Carriers of certain HLA class II alleles, e.g., DRB1*1501 and DQB1*0602, are more prone to HPV 16 infection and cervical carcinoma, whereas other alleles, e.g., DRB1*1301 and DQB1*0603, render carriers less susceptible to the disease. In our study comprising 484 cases and 601 controls, we examine the effect of HLA class II alleles on viral load of the oncogenic types HPV 18/45 and HPV 31 and risk of developing cervical carcinoma in situ. We find that carriers of the commonly reported protective DRB1*1301 and DQB1*0603 alleles have lower HPV 18/45 load compared to noncarriers and a lower risk of developing HPV 18/45-positive cervical carcinoma. This provides further evidence that the HLA class II-mediated immune response to HPV is important for controlling viral load and outcome of an infection. ' 2005 Wiley-Liss, Inc.Key words: HLA; human papillomavirus; viral load; cervical carcinoma HPV is the major etiologic risk factor for cervical carcinoma and is found in the majority of cervical tumors. Although infection with oncogenic forms of HPV are common among young women, less than 1% of those infected develop cervical carcinoma. [1][2][3] Both the length of the infection and a high viral load several years before diagnosis have been shown to increase the risk of developing cervical dysplasia and carcinoma in situ (CIS). [4][5][6] Certain HLA class II alleles, such as DRB1*1501 and DQB1*0602, have been shown to increase the risk for cervical carcinoma, most strongly in HPV 16-positive carcinomas. [7][8][9][10][11][12][13] We have previously shown that the increased carcinoma risk primarily depends on that the alleles render carriers more susceptible to HPV16 infections. 12 In addition, carriers of these HLA susceptibility alleles had higher HPV 16 load in their cervical smears compared to HPV 16-positive noncarriers. A plausible hypothesis is that HLA is involved in the cellular immunity against HPV. Also, HLA alleles making carriers more susceptible to HPV infections are likely to be less efficient in triggering immunity and inducing viral clearance. As a consequence, carriers of susceptibility alleles harbor higher HPV load than carriers of more efficient alleles. The relation between viral load and carcinoma development has been most extensively studied for HPV 16, presumably because it is the most prevalent HPV type in cervical tumors throughout most of the world. 1 We have previously examined the effect of HPV 18/45 and HPV 31 viral load on the risk for cervical CIS. 14 Our results showed that higher viral load of HPV 18/45 or HPV 31 increases the risk of CIS, although the risk magnitude is less than that observed for HPV 16. Therefore, it is possible that HLA alleles could influence carcinoma development by affecting viral load also for other HPV types besides HPV 16.A meta analysis demonstrated a protective effect of the DRB1*1301 and DQB1*0603 alleles against development of cervical carcinoma in 18 ...

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Section: Discussionsupporting

confidence: 92%

HLA class II allele control of HPV load in carcinoma in situ of the cervix uteri

Beskow

Moberg

Gyllensten

2005

Intl Journal of Cancer

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“…Cells were transiently transfected using a pCIneo E5-HA expression vector (Ashrafi et al, 2005) (HaCaT E5) (a) HaCaT cells were transiently transfected using pCI-neo-E5-HA expression vector (HaCaT E5) or using the empty vector alone (HaCaT pCI-neo). After 24 h from transfection, 16E5 expression was assessed by qualitative PCR (left panel, top) and b-actin mRNA was used as internal control: while the 16E5 band is visible only in HaCaT E5 cells, the band corresponding to actin is detected in both RT þ samples.…”

Section: Hpv 16e5 Expression Does Not Affect Kgfr Internalization Butmentioning

confidence: 99%

“…HaCaT cells were transiently transfected or co-transfected with pCI-neo empty vector or pCI-neo containing human KGFR cDNA or with pCI-neo containing 16E5-HA (Ashrafi et al, 2005) using jetPEI DNA Transfection Reagent (Polyplus-transfection, New York, NY, USA) according to the manufacturer's instructions. Transfected cells were collected 24 h after transfection for evaluation of protein expression and internalization assays.…”

Section: Cells and Treatmentsmentioning

confidence: 99%

HPV16 E5 affects the KGFR/FGFR2b-mediated epithelial growth through alteration of the receptor expression, signaling and endocytic traffic

et al. 2011

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The E5 oncoprotein of the human papillomavirus type 16 (HPV16 E5) cooperates in cervical carcinogenesis and in epithelial transformation deregulating cell growth, survival and differentiation through the modulation of growth factor receptors. Among the epithelial receptor tyrosine kinases, the keratinocyte growth factor receptor/ fibroblast growth factor receptor 2b (KGFR/FGFR2b) is a major paracrine mediator of epithelial homeostasis and appears to have an unique and unusual role in epithelial tissues, exerting a tumor-suppressive function in vitro and in vivo. With the aim to better elucidate the molecular events involved in the pathological activity of 16E5, we investigated if the viral protein would be able to affect the KGFR expression, signaling and turnover by interference with its degradative and recycling endocytic pathways. Quantitative reverse transcriptase-PCR and biochemical approaches on human keratinocytes transfected with 16E5-HA showed that E5 protein is able to induce KGFR down-modulation at both transcript and protein levels. Immunofluorescence microscopy in double-transfected cells expressing both E5 and KGFR revealed that the viral protein alters the receptor endocytic trafficking and triggers its endosomal sorting to the indirect juxtanuclear recycling pathway. The shift from lysosomal degradation to recycling at the plasma membrane correlates with a reduced phosphorylation of the fibroblast growth factor receptor substrate-2a tyrosine 196, the major docking site for Grb2-Cbl complexes responsible for receptor ubiquitination and degradation. 5 0 -Bromo-deoxyuridine incorporation assay demonstrated that expression of 16E5 induces a decrease in the growth response to the receptor ligands as a consequence of KGFR down-modulation, suggesting that 16E5 might have a role on HPV infection in perturbing the KGFR-mediated physiological behavior of confluent keratinocytes committed to differentiation.

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“…60 Furthermore, the E5 early protein of HPV can also cause retention of MHC class I molecules in the Golgi apparatus, thereby preventing their transport to the cell surface. 61,62 However, the mechanism of MHC class I antigen retention by E5 is not well understood.…”

Section: Retention Of Mhc Class I Molecules In Subcellular Compartmentsmentioning

confidence: 99%

Molecular mechanisms of HLA class I antigen abnormalities following viral infection and transformation

Seliger

Ritz

Ferrone

2005

Intl Journal of Cancer

113

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In humans as in other animal species, CD81 cytotoxic T lymphocytes (CTLs) play an important if not the major role in controlling virus-infected and malignant cell growth. The interactions between CD81 T cells and target cells are mediated by human leukocyte antigen (HLA) class I antigens loaded with viral and tumor antigen-derived peptides along with costimulatory receptor/ligand stimuli. Thus, to escape from CD8 1 T-cell recognition and destruction, viruses and tumor cells have developed strategies to inhibit the expression and/or function of HLA class I antigens. In contrast, cells with downregulated MHC class I surface expression can be recognized by NK cells, although NK cell-mediated lysis could be abrogated by the expression of inhibiting NK cell receptors. This review discusses the molecular mechanisms utilized by viruses to inhibit the formation, transport and/or expression of HLA class I antigen/peptide complexes on the cell surface. The knowledge about viral interference with MHC class I antigen presentation is not only crucial to understand the pathogenesis of viral diseases, but contributes also to the design of novel strategies to counteract the escape mechanisms utilized by viruses. These investigations may eventually lead to the development of effective immunotherapies to control viral infections and virus-associated malignant diseases. ' 2005 Wiley-Liss, Inc.

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

Cited by 189 publications

References 51 publications

HLA class II allele control of HPV load in carcinoma in situ of the cervix uteri

HLA class II allele control of HPV load in carcinoma in situ of the cervix uteri

HPV16 E5 affects the KGFR/FGFR2b-mediated epithelial growth through alteration of the receptor expression, signaling and endocytic traffic

Molecular mechanisms of HLA class I antigen abnormalities following viral infection and transformation

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