A population-based prospective study on obesity-related non-communicable diseases in northern Iran: rationale, study design, and baseline analysis.

Background: Iran is facing an epidemiological transition with the increasing burden of non-communicable diseases, such as obesity-related disorders and cardiovascular diseases (CVDs). We conducted a population-based prospective study to assess the prevalence and incidence rates of CVDs and obesity-related metabolic disorders and to evaluate the predictive ability of various CVD risk assessment tools in an Iranian population. Method: We enrolled 5,799 participants in Amol, a city in northern Iran, in 2009-2010 and carried out the first repeated measurement (RM) after seven years (2016-2017). For all participants, demographic, anthropometric, laboratory, hepatobiliary imaging, and electrocardiography data have been collected in the enrollment and the RM. After enrollment, all participants have been and will be followed up annually for 20 years, both actively and passively. Results: We adopted a multidisciplinary approach to overcome barriers to participation and achieved a 7-year follow-up success rate of 93.0% with an active follow-up of 5,394 participants aged 18-90 years. In the RM, about 64.0% of men and 81.2% of women were obese or overweight. In 2017, about 16.2% and 5.2% of men had moderate or severe non-alcoholic fatty liver disease, while women had a significantly higher prevalence of metabolic syndrome (35.9%), and type 2 diabetes mellitus (20.9%) than men. Of 160 deceased participants, 69 cases (43.1%) died due to CVDs over seven years. Conclusion: The most prevalent obesity-related chronic disease in the study was metabolic syndrome. Across the enrollment and RM phases, women exhibited a higher prevalence of obesity-related metabolic disorders. Focusing on obesity-related metabolic disorders in a population not represented previously and a multidisciplinary approach for enrolling and following up were the strengths of this study. The study outcomes offer an evidence base for future research and inform policies regarding non-communicable diseases in northern Iran.

Regulatory Effect of Ficus carica Latex on Cell Cycle Progression in Human Papillomavirus-Positive Cervical Cancer Cell Lines: Insights from Gene Expression Analysis.

Cervical cancer presents a significant global health concern with high-risk human papillomaviruses (HPVs) identified as the main cause of this cancer. Although current treatment methods for cervical cancer can eliminate lesions, preventing metastatic spread and minimizing tissue damage remain a major challenge. Therefore, the development of a safer and innovative therapeutic approach is of the utmost importance. Natural products like fig latex, derived from the Ficus carica tree, have demonstrated promising anti-cancer properties when tested on cervical cancer cell lines. However, the specific mechanisms by which fig latex exerts its effects are still unknown. In this study, we conducted RNA-Seq analysis to explore how fig latex may counteract carcinogenesis in HPV-positive cervical cancer cell lines, namely, CaSki (HPV type 16-positive) and HeLa (HPV type 18-positive). Our results from this investigation indicate that fig latex influences the expression of genes associated with the development and progression of cervical cancer, including pathways related to "Nonsense-Mediated Decay (NMD)", "Cell Cycle regulation", "Transcriptional Regulation by TP53", and "Apoptotic Process". This selective impact of fig latex on cancer-related pathways suggests a potential novel therapeutic approach for HPV-related cervical cancer.

Ficus carica Latex Modulates Immunity-Linked Gene Expression in Human Papillomavirus Positive Cervical Cancer Cell Lines: Evidence from RNA Seq Transcriptome Analysis.

Cervical carcinogenesis is the leading cause of cancer-related deaths in women, and the role of high-risk human papillomavirus (HR-HPV) as a possible risk factor in the development of this cancer is well recognized. Despite the availability of multi-therapeutic approaches, there is still major concern regarding the prevention of metastatic dissemination and excessive tissue injuries. Therefore, it is imperative to develop a safer and more efficient treatment modality. Ficus carica, a natural plant, has shown potential therapeutic properties through its fruit latex when applied to HPV-positive cervical cancer cell lines. However, the mechanisms of action of Ficus carica (fig) latex are not well understood. This study aims to provide a deeper insight into the biological activities of fig latex on human cervical cancer cell lines expressing high-risk HPV types 16 and 18. The data obtained from this study reveal that fig latex influences the expression of genes involved in "Class I MHC-mediated antigen presentation" as well as "Antigen processing: Ubiquitination and Proteasome degradation". These genes play a crucial role in host immune surveillance and the resolution of infection. Notably, Western blot analysis corroborated these findings, demonstrating an increase in the expression of MHC class I in HeLa cells after fig latex treatment. Findings from this study suggest that fig latex may enhance T cell responses against oncogenic HPV, which could be beneficial for the clearance of early-stage cancer.

Detection of high-risk Human Papillomavirus in prostate cancer from a UK based population.

Human papillomavirus (HPV) infection is one of the sexually transmitted diseases which have been implicated in the etiology of multiple cancers. To date, several studies have been conducted to evaluate the incidence of high-risk (HR) HPV in prostate cancer (PCa) which have generated widely conflicting data. Hence, this leaves a lack of awareness on the causal role of persistent HPV infection in the development of PCa. Although this has been investigated in a handful of countries, to the best of our knowledge, no prior studies have been conducted in the UK. In this study, polymerase chain reaction (PCR) and Sanger sequencing were implemented to analyze a total of 49 fresh prostate specimens (35 benign and 14 malignant specimens) for the presence of viral DNA of 12 HR-HPV types. Data obtained confirmed the presence of HR-HPV in 32.7% of analyzed benign and malignant prostate tissues with HPV 35 being identified as the most frequent type. Moreover, HR-HPV positivity rate was found to be higher in abnormal prostate tissues (adenocarcinoma and benign with prostatitis) compared those with normal prostate condition. Using immunohistochemistry, we have confirmed the expression of HPV E7 protein in prostate tissues positive for HPV DNA. This observation, the first reported from a UK population, suggests that the presence of HPV in prostate tissue is likely to be a related factor in the progression of certain cases of prostate cancer.

Scoring systems of metabolic syndrome and prediction of cardiovascular events: A population based cohort study.

BACKGROUND AND AIMS: Continuous scoring systems were developed versus traditional dichotomous approaches to define metabolic syndrome. The current study was carried out to evaluate the ability of scoring systems to predict fatal and nonfatal cardiovascular events. MATERIALS AND METHODS: The data of 5147 individuals aged 18 years or more obtained from a population-based cohort study were analyzed. The occurrence of atherosclerotic cardiovascular disease (ASCVD) in the period of 7 years follow-up was considered as the associated outcome. Joint Interim Statement (JIS) definition, as a traditional definition of metabolic syndrome (MetS), and two versions of MetS scoring systems, based on standardized regression weights from structural equation modeling (SEM) and simple method for quantifying metabolic syndrome (siMS) were considered as potential predictors. RESULTS: The scoring systems, particularly, based on SEM, were observed to have a significant association with composite cardiovascular events (HR = 1.388 [95% CI = 1.153-1.670], p = .001 in men and HR = 1.307 [0.95% CI = 1.120-1.526] in women) in multiple Cox proportional hazard regression analyses, whereas the traditional definition of MetS did not show any significant association. While both two scoring systems showed acceptable predictive abilities for cardiovascular events in women (MetS score based on SEM: area of under curve [AUC] = 0.7438 [95% CI = 0.6195-0.7903] and siMS: AUC = 0.7207 [95% CI = 0.6676-0.7738]), the two systems were not acceptable for identifying risk in men. CONCLUSION: Unlike the dichotomous definition of MetS, the scoring systems showed an independent association with cardiovascular events. Scoring systems, particularly those based on SEM, may be useful for the prediction of cardiovascular events in women.

The Ability of the Framingham Steatosis Index (FSI) to Predict Non-alcoholic Fatty Liver Disease (NAFLD): A Cohort Study.

BACKGROUND: The utilization of indexes for the diagnosis of non-alcoholic fatty liver disease (NAFLD) can be valuable. This study was conducted to determine the ability of the Framingham steatosis index (FSI) to distinguish between people with NAFLD and those without and to predict people at risk of NAFLD to establish the need for lifestyle modifications in such individuals. METHODS: Our study was conducted in two phases from 2009-2010 (phase I) to 2016-2017 (phase II). A total of 4670 people in northern Iran were included. NAFLD was diagnosed by ultrasound. The FSI was calculated based on age, sex, hypertension, diabetes mellitus status, liver enzyme levels and triglyceride levels. Receiver operating characteristic (ROC) analysis was conducted to determine the discriminatory and predictive abilities of the FSI. To remove the confounding effects of potential mediators, logistic regression was performed in which NAFLD was considered the outcome and the FSI as the predictor. RESULTS: The odds ratios of the FSI when the outcome was the prevalence of NAFLD in phase I and when the outcome was new cases of NAFLD from 2009-2010 to 2016-2017 were 4.909 (4.243-5.681) and 2.453 (2.024-2.972), respectively (P<0.001). The areas under the curve (AUCs) for the discriminatory and predictive abilities of the FSI were 0.8421 (95% CI: 0.8314-0.8527) and 0.7093 (95% CI: 0.6863-0.7322), respectively. CONCLUSION: The FSI has a strong ability to diagnose NAFLD while it has an acceptable ability to predict the occurrence of new cases of NAFLD.

Signal transduction pathway mutations in gastrointestinal (GI) cancers: a systematic review and meta-analysis.

The present study was conducted to evaluate the prevalence of the signaling pathways mutation rate in the Gastrointestinal (GI) tract cancers in a systematic review and meta-analysis study. The study was performed based on the PRISMA criteria. Random models by confidence interval (CI: 95%) were used to calculate the pooled estimate of prevalence via Metaprop command. The pooled prevalence indices of signal transduction pathway mutations in gastric cancer, liver cancer, colorectal cancer, and pancreatic cancer were 5% (95% CI: 3-8%), 12% (95% CI: 8-18%), 17% (95% CI: 14-20%), and 20% (95% CI: 5-41%), respectively. Also, the mutation rates for Wnt pathway and MAPK pathway were calculated to be 23% (95% CI, 14-33%) and 20% (95% CI, 17-24%), respectively. Moreover, the most popular genes were APC (in Wnt pathway), KRAS (in MAPK pathway) and PIK3CA (in PI3K pathway) in the colorectal cancer, pancreatic cancer, and gastric cancer while they were beta-catenin and CTNNB1 in liver cancer. The most altered pathway was Wnt pathway followed by the MAPK pathway. In addition, pancreatic cancer was found to be higher under the pressure of mutation compared with others based on pooled prevalence analysis. Finally, APC mutations in colorectal cancer, KRAS in gastric cancer, and pancreatic cancer were mostly associated gene alterations.

Non-alcoholic fatty liver disease is not independent risk factor for cardiovascular disease event: A cohort study.

BACKGROUND: There are no consistent results between previous studies for an independent association between non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD) events. AIM: To determine if there is an independent association between NAFLD and CVD events. METHODS: In the present study, valid outcome data of 4808 subjects were available for phase 2 of our cohort study. These subjects had been followed up for seven years from phase 1, beginning in 2009-2010 to phase 2 during 2016-2017. Simple and multiple Cox proportional models were used to determine the association between NAFLD in the primary phase of the cohort and subsequent fatal and non-fatal CVD events during follow-up. RESULTS: The incidence of non-fatal CVD events in males with NAFLD was significantly higher (P = 0.004) than in males without NAFLD. A positive association was demonstrated between NAFLD and non-fatal CVD events in males (Hazard ratio = 1.606; 95%CI: 1.166-2.212; P = 0.004) by the simple Cox proportional hazard model, but no independent association was detected between these in the multiple Cox models. CONCLUSION: No independent association was detected between NAFLD and CVD. It is likely that diabetes mellitus and age may be the principle mediators in this regard.

Prevalence and Type Distribution of High-Risk Human Papillomavirus (HPV) in Breast Cancer: A Qatar Based Study.

Human papillomavirus (HPV) has been implicated in the etiology of a variety of human cancers. Studies investigating the presence of high-risk (HR) HPV in breast tissue have generated considerable controversy over its role as a potential risk factor for breast cancer (BC). This is the first investigation reporting the prevalence and type distribution of high-risk HPV infection in breast tissue in the population of Qatar. A prospective comparison blind research study herein reconnoitered the presence of twelve HR-HPV types' DNA using multiplex PCR by screening a total of 150 fresh breast tissue specimens. Data obtained shows that HR-HPV types were found in 10% of subjects with breast cancer; of which the presence of HPV was confirmed in 4/33 (12.12%) of invasive carcinomas. These findings, the first reported from the population of Qatar, suggest that the selective presence of HPV in breast tissue is likely to be a related factor in the progression of certain cases of breast cancer.

Biological activities of Ficus carica latex for potential therapeutics in Human Papillomavirus (HPV) related cervical cancers.

Infection caused by high-risk human papillomaviruses (HPVs) are implicated in the aetiology of cervical cancer. Although current methods of treatment for cervical cancer can ablate lesions, preventing metastatic disseminations and excessive tissue injuries still remains a major concern. Hence, development of a safer and more efficient treatment modality is of vital importance. Natural products from plants are one of the principal sources of precursors to lead compounds with direct pharmaceutical application across all disease classes. One of these plants is Ficus carica, whose fruit latex, when applied on HPV-induced skin warts, has shown potential as a possible cure for this virus related lesions. This study explores the in vitro biological activities of fig latex and elucidates its possible mechanisms of action on cervical cancer cell lines CaSki and HeLa positive for HPV type 16 and 18, respectively. Our data shows that fig latex inhibits properties that are associated with HPV-positive cervical cancer transformed cells such as rapid growth and invasion and substantially downregulated the expression of p16 and HPV onco-proteins E6, E7. These findings suggest Ficus carica latex has the potential to be used in the development of therapeutic modalities for the possible treatment, cure and prevention of HPV related cervical cancer.

Synergistic effects of various Her inhibitors in combination with IGF-1R, C-MET and Src targeting agents in breast cancer cell lines.

Overexpression of HER2 has been reported in around 25% of human breast cancers. Despite recent advances in HER2 targeted therapy, many patients still experience primary and secondary resistance to such treatments, the mechanisms for which are poorly understood. Here, we investigated the sensitivity of a panel of breast cancer cell lines to treatment with various types of HER-family inhibitors alone or in combination with other tyrosine kinase inhibitors or chemotherapeutic agents. We found that treatment with the second-generation irreversible HER-family inhibitors, particularly afatinib and neratinib, were more effective than treatment with the first-generation reversible inhibitors in inhibiting growth, migration and downstream cell signalling in breast cancer cells. Of the three HER2 overexpressing cell lines in this panel, SKBr3 and BT474 were highly sensitive to treatment with HER-family inhibitors, while MDA-MB-453 was comparatively resistant. Combinations of HER-family inhibitors with NVP-AEW541, dasatinib or crizotinib (inhibitors of IGF-1R, Src and c-Met/ALK, respectively) led to synergistic effects in some of the cell lines examined. In particular, treatment with a combination of Src and HER-family member inhibitors resulted in synergistic growth inhibition of MDA-MB453 cells, implicating Src as a mediator of resistance to HER2-targeting agents. Our results suggest that combining HER-family inhibitors with other TKIs such as dasatinib may have therapeutic advantages in certain breast cancer subtypes and warrants further investigation.

Association of High Risk Human Papillomavirus and Breast cancer: A UK based Study.

Infection by human papillomaviruses (HPVs) has been implicated in the aetiology of a variety of cancers. Studies evaluating the presence of HPVs in breast cancer (BC) have generated considerable controversy. To date, most studies have focused on the presence of viral DNA in BC; however there are important gaps in evidencing the role of HPV persistence in the invasiveness of BC. While these studies have been conducted in several countries, none, on the presence and biological activity of high risk (HR) HPV in BC has been done in the UK. Hence, we aimed to investigate these gaps by screening a total of 110 fresh breast tissue specimens from UK patients for the presence of twelve HR-HPV types DNA using PCR and Sanger sequencing. Samples positive for HPV-DNA were screened for viral oncoprotein expression using western blot and dot blot. Data obtained showed the presence of HR-HPVs in 42% of breast tissues of which the viral activity was only confirmed in a number of invasive carcinomas (5/26). This finding, the first to report in the UK, suggests that the selective expression of viral oncoprotein in invasive cases may propose a role for HR-HPVs in the development of some types of BC.

A systematic review and meta-analysis of seroprevalence of varicella zoster virus: A nationwide population-based study.

Varicella zoster virus (VZV) causes chicken pox as a primary infection following which it becomes latent in neurons. It may then reactivate to cause shingles (herpes zoster). Severity of lesions and VZV pathogenicity are depended on the host's immune response and variant in VZV Dr Athina Myrto ChioniIdentification of VZV seroprevalance rate in general population may lead to develop new health strategic managements such as vaccination. Therefore, we aimed to provide a systematic review of the seroprevalence of VZV infection among Iranian population and estimate age- and gender- specific prevalence of VZV. Keywords "seroprevalence"; "varicella zoster virus" and "Iran"; were searched in international electronic databases and also in national Persian databases. Twenty two pooled studies among 262 total studies containing (240 published articles; 18 dissertations; and 4 proceedings abstracts) from 1992 to 2014 with total sample size of 7867 individuals were included in the final review. Data was analyzed using random effect method. The heterogeneity was calculated using I-square statistics The overall IgG seroprevalence rate of VZV infection in general population of Iran was 78.50% (95% CI; 77.74%-79.25%). There was significant heterogeneity among the studies (P<0.0001; I2=99.4%). Furthermore, the relative risk of VZV infection is high in females (80.47%, 95% CI; 79.40%-81.54%) and older adults (95.30%, 95% CI; 94.11% -96.48%). Our results may represent a true background and estimation of VZV infection in Iran and generate the cost-benefits immunization program. Moreover, the ensuing data suggests further attention on disease seroprevalence in order to obtain efficient data for therapeutic intervention targeted against VZV.

Prevalence and type distribution of high-risk human papillomavirus in patients with cervical cancer: a population-based study.

BACKGROUND: Cervical cancer is the greater cause of cancer death in women in many developing countries. Persistent infection with human papilloma virus (HPV), primarily high risk types 16 and 18, is recognized as a causal and essential factor for the development of cervical cancer. We aimed to determine the distribution of high-risk HPV genotypes in archival biopsies with cervical carcinoma in patients from Mazandaran Province, Northern Iran. METHODS: A total of 98 paraffin-embedded cervical samples consisted of 63 Squamous Cell Carcinomas (SCC), 4 Adenocarcinomas, 19 Cervical Interaepithelial Neoplasia grade I (CIN-I), 4 CIN-II and 8 CIN-III diagnosed during 2009-2011, were selected to perform high risk HPV genotyping using AmpliSens(R) HPV HCR DNA genotyping kit. The prevalence of HPV infections was assessed in low and high grade cervical lesions by age. RESULTS: Of the 98 cervical samples analysed by DNA PCR, 78 (79.59%) were positive for HPV DNA. HPV was detected in the 52 of SCC, 4 of Adenocarcinomas, 14 of CIN-I, 4 of CIN-II, and 4 of CIN-III for HPV. From the 78 HPV positive samples, 23 (29.5%) samples were positive for HPV type 16, 32 (41%) were positive for HPV 18, 19 (24.4%) were positive for HPV 45, and 4 (5.1%) of cervical specimens were positive for HPV 39. CONCLUSIONS: This study provides valuable baseline data for future assessment of the impact of current prophylactic vaccination programs that is protective against the two most common oncogenic types of HPV found in cervical cancer, HPV-16 and HPV-18, but not against other high-risk mucosal HPVs, 39 and 45, reported in this population.

Effects of human papillomavirus type 16 E5 deletion mutants on epithelial morphology: functional characterization of each transmembrane domain.

Human papillomavirus type 16 (HPV-16) is the cause of cervical cancer. The HPV genome encodes three transforming proteins, E5, E6 and E7. E6 and E7 are the main transforming proteins of HPV, while the role of E5 is still poorly understood. Using three dimensional organotypic raft cultures we show that HaCaT human keratinocytes expressing HPV-16 E5 form a very perturbed epithelium, with simultaneous hyperkeratinization of some cells and defective differentiation of other cells. The basal layer is disturbed and many cells invade the collagen matrix. Many cells among the differentiated layers show characteristics of basal cells: progression through the cell cycle, expression of cytokeratin 14, lack of cytokeratin 1 and production of matrix metalloproteases (MMP). Using deletion mutants which encompass the three hydrophobic domains of E5, we have assigned the ability to promote invasion of the matrix to the first hydrophobic domain, and the capacity to induce MMP9 to the C-terminal four amino acids. We also show that invasion and production of MMP9 can be dissociated, as mutants that are still capable of invasion do not produce MMP9 and vice versa.

All 4 di-leucine motifs in the first hydrophobic domain of the E5 oncoprotein of human papillomavirus type 16 are essential for surface MHC class I downregulation activity and E5 endomembrane localization.

The E5 oncoprotein of human papillomavirus type 16 downregulates surface MHC Class I and interacts with the heavy chain of the MHC complex via the first hydrophobic domain, believed to form the first helical transmembrane region (TM1) of E5. TM1 contains 4 equally spaced di-leucine (LL1-LL4) motifs. Di-leucine motifs have been implicated in protein-protein interactions and as localization signals. To see if any of the 4 di-leucine motifs of TM1 are involved in MHC downregulation by E5, we mutated each LL pair into valine pairs (VV1-VV4), as mutation of leucine to valine is not expected to cause major structural alterations in E5. We found that all 4 mutations disrupted the intracellular location of E5 and abrogated its MHC I downregulating activity; however VV2 and VV4 mutants were still able to interact physically with the MHC I heavy chain (HC) in vitro, while VV1 and VV3 mutants had lost this activity. We conclude that LL1 and LL3 are necessary for the interaction with HC, but LL2 and LL4 are not. However all 4 LL motifs are responsible for the proper localization of E5 in the Golgi/ER, and the displacement of E5 from this location contributes to the abrogation of MHC I downregulation. LL1 and LL3 motifs are expected to be on one face of the TM1 helix and LL2 and LL4 on the opposite face. We propose that E5 interacts with HC via LL1 and LL3 and that all 4 di-leucine motifs act as a targeting signal.

E5 protein of human papillomavirus 16 downregulates HLA class I and interacts with the heavy chain via its first hydrophobic domain.

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.

Three rare cases of anthrax arising from the same source.

Anthrax is an acute bacterial infection caused by Bacillus anthracis. Humans become infected under natural conditions by contact with infected animals or contaminated animal products. About 95% of human anthrax is cutaneous and 5% respiratory. Gastrointestinal anthrax is very rare, and has been reported in less than 1% of all cases. Anthrax meningitis is a rare complication of any of the other three forms of disease. We report three rare cases of anthrax (gastrointestinal, oropharyngeal and meningitis) arising from the same source. The three patients were from a single family and were admitted with different clinical pictures after the ingestion of half-cooked meat from a sick sheep. These cases emphasize the need for awareness of anthrax in the differential diagnosis in areas where the disease remains endemic.

Similarities and differences between the E5 oncoproteins of bovine papillomaviruses type 1 and type 4: cytoskeleton, motility and invasiveness in E5-transformed bovine and mouse cells.

Bovine papillomaviruses (BPVs) are oncogenic viruses. In cattle, BPV-1/2 is associated with urinary bladder cancer and BPV-4 with upper GI tract cancer. BPV E5 is a small hydrophobic protein localised in the endoplasmic reticulum (ER) and Golgi apparatus (GA). E5 is the major transforming protein of BPVs, capable of inducing cell transformation in cultured mouse fibroblasts and, in cooperation with E7, in primary bovine cells. E5-induced cell transformation is accompanied by activation of several cellular protein kinases, including growth factor receptors, and alkalinisation of endosomes and GA. We have reported that BPV E5 causes swelling and fragmentation of the GA and extensive vacuolisation of the cytoplasm. We now show that E5 from both BPV-1 and BPV-4 disturbs the actin cytoskeleton and focal adhesions in transformed bovine cells, where these morphological and behavioural characteristics are accompanied by hyperphosphorylation of the cellular phosphotyrosine kinase c-src. Both BPV-1 and BPV-4 E5 increase the motility of transformed mouse cells, but only BPV-1 E5 causes transformed mouse cells to penetrate a matrigel matrix. BPV-1 transformed mouse cells, but not BPV-4 transformed mouse cells, have hyperhpsphorylated c-src.

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

Papillomaviruses have evolved mechanisms that result in escape from host immune surveillance. The E5 protein is expressed early in papillomavirus infection in the deep layers of the infected epithelium. It is localized to the Golgi apparatus (GA) and endoplasmic reticulum. The E5 protein of bovine papillomavirus (BPV) impairs the synthesis and stability of major histocompatibility (MHC) class I complexes and prevents their transport to the cell surface due to retention in the GA. Here we show that human papillomavirus type 16 (HPV-16) E5 also causes the retention of MHC (HLA) class I complexes in the GA and impedes their transport to the cell surface, which is rescued by treatment with interferon. Unlike BPV E5, HPV-16 E5 does not affect the synthesis of HLA class I heavy chains or the expression of the transporter associated with antigen processing TAP. These results show that downregulation of surface MHC class I molecules is common to both BPV and HPV E5 proteins. Moreover, we determined that HPV-16 E5 downregulates surface expression of HLA-A and HLA-B, which present viral peptides to MHC class I-restricted cytotoxic T lymphocytes (CTLs), but not the natural killer (NK) cell inhibitory ligands HLA-C and HLA-E. Selective downregulation of cell surface HLA class I molecules may allow the virus to establish infection by avoiding immune clearance of virus-infected cells by both CTLs and NK cells.