Human Papillomavirus Proteins Research Articles

Triple lysine and nucleosome-binding motifs of the viral IE19 protein are required for human cytomegalovirus S-phase infections.

Herpesvirus genomes are maintained as extrachromosomal plasmids within the nuclei of infected cells. Some herpesviruses persist within dividing cells, putting the viral genome at risk of being lost to the cytoplasm during mitosis because karyokinesis (nuclear division) requires nuclear envelope breakdown. Oncogenic herpesviruses (and papillomaviruses) avoid genome loss during mitosis by tethering their genomes to cellular chromosomes, thereby ensuring viral genome uptake into newly formed nuclei. These viruses use viral proteins with DNA- and chromatin-binding capabilities to physically link viral and cellular genomes together in a process called tethering. The known viral tethering proteins of human papillomavirus (E2), Epstein-Barr virus (EBNA1), and Kaposi's sarcoma-associated herpesvirus (LANA) each contain two independent domains required for genome tethering, one that binds sequence specifically to the viral genome and another that binds to cellular chromatin. This latter domain is called a chromatin tethering domain (CTD). The human cytomegalovirus UL123 gene encodes a CTD that is required for the virus to productively infect dividing fibroblast cells within the S phase of the cell cycle, presumably by tethering the viral genome to cellular chromosomes during mitosis. The CTD-containing UL123 gene product that supports S-phase infections is the IE19 protein. Here, we define two motifs in IE19 required for S-phase infections: an N-terminal triple lysine motif and a C-terminal nucleosome-binding motif within the CTD.IMPORTANCEThe IE19 protein encoded by human cytomegalovirus (HCMV) is required for S-phase infection of dividing cells, likely because it tethers the viral genome to cellular chromosomes, thereby allowing them to survive mitosis. The mechanism through which IE19 tethers viral genomes to cellular chromosomes is not understood. For human papillomavirus, Epstein-Barr virus, and Kaposi's sarcoma-associated herpesvirus, viral genome tethering is required for persistence (latency) and pathogenesis (oncogenesis). Like these viruses, HCMV also achieves latency, and it modulates the properties of glioblastoma multiforme tumors. Therefore, defining the mechanism through which IE19 tethers viral genomes to cellular chromosomes may help us understand, and ultimately combat or control, HCMV latency and oncomodulation.

Preclinical evaluation of two phylogenetically distant arenavirus vectors for the development of novel immunotherapeutic combination strategies for cancer treatment

BackgroundEngineered arenavirus vectors have recently been developed to leverage the body’s immune system in the fight against chronic viral infections and cancer. Vectors based on Pichinde virus (artPICV) and lymphocytic...

Antibodies against high-risk human papillomavirus proteins as markers for noncervical HPV-related cancers in a Black South African population, according to HIV status.

Human papillomavirus (HPV) proteins may elicit antibody responses in the process toward HPV-related malignancy. However, HPV seroepidemiology in noncervical HPV-related cancers remains poorly understood, particularly in populations with a high prevalence of human immunodeficiency virus (HIV). Using a glutathione S-transferase-based multiplex serology assay, antibodies against E6, E7 and L1 proteins of HPV16 and HPV18 were measured in sera of 535 cases of noncervical HPV-related cancers (anal (n = 104), vulval (n = 211), vaginal (n = 49), penile (n = 37) and oropharyngeal (n = 134)) and 6651 non-infection-related cancer controls, from the Johannesburg Cancer Study that recruited Black South African with newly diagnosed cancer between 1995 and 2016. Logistic and Poisson regression models were used to calculate adjusted odds ratios (aOR) and prevalence ratios (aPR) and 95% confidence intervals (CI) in cases versus controls. HPV16 E6 was more strongly associated with noncervical HPV-related cancers than HPV16 L1 or E7, or HPV18 proteins: anal (females (HPV16 E6 aOR = 11.50;95%CI:6.0-22.2), males (aOR = 10.12;95%CI:4.9-20.8), vulval (aOR = 11.69;95%CI:7.9-17.2), vaginal (aOR = 10.26;95%CI:5.0-21), penile (aOR = 18.95;95%CI:8.9-40), and oropharyngeal (females (aOR = 8.95;95%CI:2.9-27.5), males (aOR = 3.49;95%CI:1.8-7.0)) cancers. HPV16-E6 seropositivity ranged from 24.0% to 35.1% in anal, vulval, vaginal and penile cancer but was significantly lower (11.2%) in oropharyngeal cancer. After adjustment for HIV, prevalence of which increased from 22.2% in 1995-2005 to 54.1% in 2010-2016, HPV16 E6 seropositivity increased by period of diagnosis (aPR for 2010-2016 vs. 1995-2006 = 1.84;95%CI:1.1-3.0). Assuming HPV16 E6 seroprevalence reflects HPV attributable fraction, the proportion of certain noncervical-HPV-related cancers caused by HPV is increasing over time in South Africa. This is expected to be driven by the increasing influence of HIV.

Designing a Novel Multiepitope Vaccine from the Human Papilloma Virus E1 and E2 Proteins for Indonesia with Immunoinformatics and Molecular Dynamics Approaches.

One of the deadliest malignant cancer in women globally is cervical cancer. Specifically, cervical cancer is the second most common type of cancer in Indonesia. The main infectious agent of cervical cancer is the human papilloma virus (HPV). Although licensed prophylactic vaccines are available, cervical cancer cases are on the rise. Therapy using multiepitope-based vaccines is a very promising therapy for cervical cancer. This study aimed to develop a multiepitope vaccine based on the E1 and E2 proteins of HPV 16, 18, 45, and 52 using in silico. In this study, we develop a novel multiepitope vaccine candidate using an immunoinformatic approach. We predicted the epitopes of the cytotoxic T lymphocyte (CTL) and helper T lymphocyte (HTL) and evaluated their immunogenic properties. Population coverage analysis of qualified epitopes was conducted to determine the successful use of the vaccine worldwide. The epitopes were constructed into a multiepitope vaccine by using AAY linkers between the CTL epitopes and GPGPG linkers between the HTL epitopes. The tertiary structure of the multiepitope vaccine was modeled with AlphaFold and was evaluated by Prosa-web. The results of vaccine construction were analyzed for B-cell epitope prediction, molecular docking with Toll like receptor-4 (TLR4), and molecular dynamics simulation. The results of epitope prediction obtained 4 CTL epitopes and 7 HTL epitopes that are eligible for construction of multiepitope vaccines. Prediction of the physicochemical properties of multiepitope vaccines obtained good results for recombinant protein production. The interaction showed that the interaction of the multiepitope vaccine-TLR4 complex is stable based on the binding free energy value -106.5 kcal/mol. The results of the immune response simulation show that multiepitope vaccine candidates could activate the adaptive and humoral immune systems and generate long-term B-cell memory. According to these results, the development of a multiepitope vaccine with a reverse vaccinology approach is a breakthrough to develop potential cervical cancer therapeutic vaccines.

Designing of a novel and potent HPV66 L1 major capsid protein-epitope based therapeutic vaccine against Human Papillomavirus (HPV): A bioinformatics approach

Aim: Oncogenic human papillomaviruses (HPV) cause various types of cancer, including cervical cancer. The main protein of HPV is capsid, targeted in many vaccine attempts. However, these vaccines do not cover enough high-risk HPV serotypes. Therefore, a low-cost potential HPV vaccine to protect against all serovars of the α-papillomaviruses family would be promising in the future. Our study aimed to develop a therapeutic epitope vaccine for HPV using bioinformatics methods. Methodology: Bioinformatics approach was followed to analyze and identify potential T-cell and B-cell dominant epitopes of HPV-66 L1 major capsid protein. Additionally, various aspects of this protein were examined, including its physico-chemical properties, and secondary and tertiary structures. These analyses helped us to design an effective HPV infection therapeutic vaccine. Results: The findings revealed that the L1 major capsid protein was unstable and hydrophilic. The secondary structure of this protein composed 39% α- helices, 17.97% β sheets and 31.80% loops. Our study demonstrated 19 dominant epitopes of HPV-66 L1 major capsid protein including 5 B-cell epitopes and 14 T-cell epitopes (10 HTL epitopes, and 4 CTL epitopes) for a novel vaccine candidate. Interpretation: This study provides a comprehensive biological information about the HPV-66 L1 major capsid protein, which will serve as a theoretical foundation for developing a multi-epitope vaccine against HPV infection. Key words: B-cell epitope, Cervical Cancer, Human papillomavirus, HPV66 L1 major capsid protein, T-cell epitope

Abstract 4719: Modulation of HR-HPV viral protein E7 by SHetA2 in cervical cancer

Abstract Introduction: The purpose of this study is to determine the effect of the chemotherapeutic sulfur heteroarotinoid A2 (SHetA2) on high-risk human papillomavirus (HR-HPV) proteins and the modulation of cell survival and proliferation in cervical cancer. Cervical cancer is caused by persistent HR-HPV infection. HR-HPV tumorigenesis is driven by its early 6 and 7 (E6, E7) oncoproteins, which increase cell proliferation and survival. Cellular pathways regulated by E6 and E7 are counter-regulated by the investigational new drug SHetA2, which is currently in phase 1 clinical trial for advanced and recurrent cancers. SHetA2 disrupts complexes of 70-kDa heat shock protein (HSP70) family members, hsc70, GRP78, and mortalin, with their client proteins. We hypothesized that SHetA2 reduces E6 and E7 levels and their binding to HSP70 chaperones in association with the reduction of cervical cancer cells and tumor growth. Methods: SHetA2 effects on specific genes and proteins in HR-HPV-positive cervical cancer cell lines and xenograft tumors were assessed by western blot, quantitative polymerase chain reaction, immunofluorescence ligation assays, and coimmunoprecipitation assays. Results: SHetA2 significantly reduced E6 and E7 mRNA, and protein levels of E7 and the E7-regulated p16, but not E6 in cervical cancer cells and xenograft tumors. MG132 inhibition of proteasome function attenuated the E7 reduction. HSP70/hsc70 proteins bound E7 and SHetA2 disrupted these complexes. Conclusions/Implications: SHetA2 reduces E7 proteins in cervical cancer cells through a mechanism that involves proteasomal degradation in association with disruption of HSP70/E7 complexes, p16 reduction, and decreased cell and tumor growth. This is the first demonstration of HSP70/E7 complexes. SHetA2-induced release of E7 from HSP70s could be causing increased susceptibility of E7 to proteasomal degradation. This data supports the development of SHetA2 and HSP70 inhibitors for cervical cancer. Citation Format: Justin Garland, Showket Hussain, Doris M. Benbrook. Modulation of HR-HPV viral protein E7 by SHetA2 in cervical cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4719.

Computational and AI-driven 3D structural analysis of human papillomavirus (HPV) oncoproteins E5, E6, and E7 reveal significant divergence of HPV E5 between low-risk and high-risk genotypes

There are over 220 identified genotypes of Human papillomavirus (HPV), and the HPV genome encodes 3 major oncogenes, E5, E6, and E7. Conservation and divergence in protein sequence and function between low-risk versus high-risk oncogenic HPV genotypes has not been fully characterized. Here, we used modern computational and structural folding algorithms to perform a comparative analysis of HPV E5, E6, and E7 between multiple low risk and high risk genotypes. We first identified significantly greater sequence divergence in E5 between low- and high-risk genotypes compared to E6 and E7. Next, we used AlphaFold to model the structure of papillomavirus proteins and complexes with high confidence, including some with no established consensus structure. We observed that HPV E5, but not E6 or E7, had a dramatically different 3D structure between low-risk and high-risk genotypes. To our knowledge, this is the first comparative analysis of HPV proteins using Alphafold artificial intelligence (AI) system. The marked differences in E5 sequence and structure in high-risk HPVs may contribute in important and underappreciated ways to the development of HPV-associated cancers.

IPSC-Derived KitD816V/Jak2V817F Double-Mutant Kitjak Cell Lines Allow Inexpensive Large-Scale Production of Enucleated Red Blood Cells in the Absence of SCF and Erythropoietin

Cultured Red Blood Cells (cRBCs) have the potential to supplement transfusion needs and to be used as drug carriers or immune tolerization agents. Several methods have been devised to amplify primary Hematopoietic Progenitor cells (HPCs) into cRBCs. Although these protocols have the potential to relieve local blood shortages, they are not ideal for large scale cRBC production because the primary HPCs must constantly be replenished. Immortalized human erythroid cell lines have been developed by overexpressing the E6/E7 proteins of human papilloma virus 16, c-Myc, Bcl-XL, Spi1 or Bmi-1. Many of these lines can be cultured for months and in some cases indefinitely, and some retain their ability to differentiate into cRBCs with rates of enucleation varying between 0.1-30%. These lines are useful as research tools and are a potential source of cells for some translational applications. Nevertheless, karyotypic instability, the cost of the media and cytokines, and cumbersome culture procedure to maintain some of these lines remain major obstacles for their large-scale use. We previously developed the Pluripotent Stem Cell Robust Erythroid Differentiation (PSC-RED) protocol to differentiate induced-pluripotent stem cells (iPSCs) into cRBCs. The PSC-RED protocol yields a large number of enucleated RBCs, does not require any albumin, and allows transferrin recycling. Despite these advantages, the PSC-RED protocol is not well-adapted for large-scale cRBC production because differentiation of an iPSC into a RBC takes up to 45 days and because of cytokine cost. To eliminate the requirement for Stem Cell Factor (SCF) and Erythropoietin (Epo) which accounts for more than 95% of total cytokine cost in the PSC-RED protocol, we have used CRSPR/cas9 technology to introduce in iPSCs the kitD816V mutation that allows the SCF receptor (the kit gene) to constitutive signal in the absence of SCF, and the Jak2V617F mutation that allows constitutive signaling through the JAK/STAT pathway in the absence of Epo. We report here that kitD816V, Jak2V617F double mutants iPSCs readily differentiate into self-renewing erythroid progenitors cells that can grow in the absence of any cytokines for >60 population doubling ( >10 19 fold expansion for >5 months) in an inexpensive culture medium containing little more than two small molecules and low amounts of recombinant transferrin. Importantly, KitJak cell lines can be reproducibly generated from iPSCs by a two-week differentiation procedure without any time lag, suggesting that no other mutations are necessary to generate these self-renewing erythroid progenitors. Indeed, we have shown using a next-generation sequencing approach that KitJak cells appear to be remarkably karyotypically stable since multiple experiments fail to detect any chromosomal aneuploidy after long-term culture. KitJak cells have an immuno-phenotype of late CFU-E/pro-Erythroblast, can be cultured at high density and can be induced to differentiate into cRBCs using a 10- to 12-day differentiation protocol that leads to a 20 to 40-fold cell amplification. The rate of enucleation is 30-40%, providing an overall yield of 7-14 RBCs per self-renewing KitJak cell. The cRBCs produced express mostly fetal hemoglobin, are slightly larger that adult cells, and have normal hemoglobin content. The development of these KitJak cell lines greatly facilitates the production of cRBCs and will pave the way to large-scale erythroid cell production for transfusion and other translational applications. As a first application, we show that the RBCs produced are fully compatible with the Immucor red blood cell typing system and can be used as reagent red blood cells.

Screening and identification of B cell epitope within the major capsid protein L1 of HPV 52, using monoclonal antibodies

The L1 protein of Human papillomavirus (HPV), the main capsid protein, induces the formation of neutralizing antibodies. In this study, HPV52 L1 protein was induced to be expressed. Monoclonal antibody (mAb) 6A7 against L1 protein were screened by cell fusion techniques. Western Blot and immunofluorescence assay (IFA) demonstrated the specificity of the mAb. The L1 protein was truncated for prokaryotic expression (N1∼N7) and Dot-ELISA showed that 6A7 recognized N3 (aa 200–350). The immunodominant regions were truncated again for expression, with 6A7 recognizing N6 (aa 251–305). The N6 proteins were further truncated and then were constructed an four-segment eukaryotic expression vector. IFA showed that 6A7 could recognize amino acid 262–279. Amino acid 262–279 was selected to be truncated into short peptides P1 and P2. Finally, Peptide-ELISA and Dot-ELISA showed that the epitope regions of mAb 6A7 were amino acid 262–273. The mAbs with defined epitopes can lay the foundation for the analysis of antigenic epitope characteristics and promote the development of epitope peptide vaccines.

Interactions among human papillomavirus proteins and host DNA repair factors differ during the viral life cycle and virus-induced tumorigenesis.

This review focuses on the impact of human papillomavirus (HPV) oncogenes on DNA repair pathways with a particular focus on how these relationships change as productive HPV infections transition to malignant lesions. We made specific efforts to incorporate advances in the understanding of HPV and DNA damage repair over the last 4 years. We apologize for any articles that we missed in compiling this report.

Association between Human Papilloma Virus (HPV) genotype and protein of retinoblastoma expression in cervical cancer

Link of Video Abstract: https://youtu.be/5Q9QmV4Qmyg Background: Regarding prevalence among females worldwide, cervical cancer ranks fourth and has a high fatality rate. Cervical cancer growth is correlated with high-risk human papillomavirus (HPV) infection. Retinoblastoma protein (pRb) is a protein that interacts with E6/E7 oncoproteins to regulate cell proliferation, differentiation, and death. Mutations on the E6/E7 protein oncogenes of high-risk HPV can disrupt this relationship. This investigation aims to establish the association between pRb expression and the HPV genotype. Methods: This observational cross-sectional study examined 43 patients diagnosed with cervical cancer at Wahidin Sudirohusodo Hospital and its network. Samples were taken using consecutive random sampling based on established criteria. HPV genotype was examined using the polymerase chain reaction (PCR) method, while pRB expression was assessed by immunohistochemical examination. The relationship between the two variables was assessed using the Chi-Square test. Results: There were 5 (11.6%) patients with HPV type 16, 14 (32.6%) with HPV type 18, 12 (27.9%) with other types of HPV and 12 (27.9%) were negative for HPV. Examination of pRb expression showed that 33 (76.7%) samples had +2 expression, 7 (16.3%) had +1 expression, and 3 (7.0%) samples had no pRb expression. The pRb expression and HPV type were not significantly correlated in this study (p = 0.410). However, pRb expression and cervical cancer clinical stage were shown to be significantly correlated (p = 0.007). Conclusion: pRb expression is more prevalent when a malignancy is more advanced. In this investigation, no association between HPV genotype and pRb expression was discovered, despite oncogene mutations being involved in the regulation mechanism of cell proliferation, differentiation, and apoptosis.

Therapeutic Efficacy of a VSV-GP-based Human Papilloma Virus Vaccine in a Murine Cancer Model

Human papilloma virus (HPV) infections are associated with almost all cervical cancers and to a lower extend also with anogenital or oropharyngeal cancers. HPV proteins expressed in HPV-associated tumors are attractive antigens for cancer vaccination strategies as self-tolerance, which is associated with most endogenous tumor-associated antigens, does not need to be overcome. In this study, we generated a live attenuated cancer vaccine based on the chimeric vesicular stomatitis virus VSV-GP, which has previously proven to be a potent vaccine vector and oncolytic virus. Genes at an earlier position in the genome more to the 3′ end are expressed stronger compared to genes located further downstream. By inserting an HPV16-derived antigen cassette consisting of E2, E6 and E7 into VSV-GP either at first (HPVp1) or fifth (HPVp5) position in VSV-GP’s genome we aimed to analyze the effect of vaccine antigen position and consequently expression level on viral fitness, immunogenicity, and anti-tumoral efficacy in a syngeneic mouse tumor model. HPVp1 expressed higher amounts of HPV antigens compared to HPVp5 in vitro but had a slightly delayed replication kinetic which overall translated into increased HPV-specific T cell responses upon vaccination of mice. Immunization with both vectors protected mice in prophylactic and in therapeutic TC-1 tumor models with HPVp1 being more effective in the prophylactic setting. Taken together, VSV-GP is a promising candidate as therapeutic HPV vaccine and first position of the vaccine antigen in a VSV-derived vector seems to be superior to fifth position.

Utilization of a cell-penetrating peptide-adaptor for delivery of human papillomavirus protein E2 into cervical cancer cells to arrest cell growth and promote cell death.

Human papillomavirus (HPV) is the causative agent of nearly all forms of cervical cancer, which can arise upon viral integration into the host genome and concurrent loss of viral regulatory gene E2. Gene-based delivery approaches show that E2 reintroduction reduces proliferative capacity and promotes apoptosis in vitro. This work explored if our calcium-dependent protein-based delivery system, TAT-CaM, could deliver functional E2 protein directly into cervical cancer cells to limit proliferative capacity and induce cell death. TAT-CaM and the HPV16 E2 protein containing a CaM-binding sequence (CBS-E2) were expressed and purified from Escherichia coli. Calcium-dependent binding kinetics were verified by biolayer interferometry. Equimolar TAT-CaM:CBS-E2 constructs were delivered into the HPV16+ SiHa cell line and uptake verified by confocal microscopy. Proliferative capacity was measured by MTS assay and cell death was measured by release of lactate dehydrogenase. As a control, human microvascular cells (HMECs) were used. As expected, TAT-CaM bound CBS-E2 with high affinity in the presence of calcium and rapidly disassociated upon its removal. After introduction by TAT-CaM, fluorescently labeled CBS-E2 was detected in cellular interiors by orthogonal projections taken at the depth of the nucleus. In dividing cells, E2 relocalized to regions associated with the mitotic spindle. Cells receiving a daily dose of CBS-E2 for 4 days showed a significant reduction in metabolic activity at low doses and increased cell death at high doses compared to controls. This phenotype was retained for 7 days with no further treatments. When subcultured on day 12, treated cells regained their proliferative capacity. Using the TAT-CaM platform, bioactive E2 protein was delivered into living cervical cancer cells, inducing senescence and cell death in a time- and dose-dependent manner. These results suggest that this nucleic acid and virus-free delivery method could be harnessed to develop novel, effective protein therapeutics.

Abstract P2-26-04: Human papillomavirus protein E6 regulates Toll like receptor-9 expression in breast cancer cells

Abstract Toll like receptor-9 (TLR9) is an innate immunity DNA-receptor, which is widely expressed in various cancers, including breast cancer. Low TLR9 expression in cancer cells was initially associated with poor prognosis among patients with triple negative breast cancer. We have now discovered a similar association also among among other breast cancer subtypes. The mechanism for TLR9-associated poor prognosis is not currently known, but our ongoing studies suggest that it may be due to poor chemotherapy responses. Regulation of TLR9 expression in breast cancer is poorly understood. It has been demonstrated that in cervical cancers, TLR9 expression is suppressed by human papillomavirus (HPV) infections. Although breast cancer is not typically considered HPV-associated, there are reports of HPV in breast cancer. The aim here was to test the hypothesis, that HPV-infections suppress TLR9 expression also in breast cancer. To study this, human breast cancer cells were infected with HPV16 E6-oncoprotein, followed by measurement of TLR9 mRNA and protein in vitro. We also aimed to compare the presence of HPV DNA with TLR9 protein expression in clinical breast cancer specimens. We further studied E6-infection effects on breast cancer proliferation, migration, and invasion. E6-infection decreased TLR9 protein expression in TNBC but not in estrogen receptor expressing (ER+) cells. E6-overexpression significantly altered breast cancer proliferation, but the impact was opposite in TNBC and ER+ cells. No effect on migration and invasion was observed. E6-transfected breast cancer cells were significantly less sensitive in vitro to chemotherapies typically used for the treatment of breast cancer in the adjuvant setting. In vivo studies are pending. HPV DNA was not detected in a pilot cohort of clinical breast cancer specimens (n=37) among Northern Finnish breast cancer specimens. These results indicate that HPV may affect breast cancer TLR9 expression and thereby breast cancer prognosis, through treatment responses. Although HPV was not detected in the small pilot set of our clinical samples, this issue needs to be further studied in larger data sets. Citation Format: Essi Parviainen, Sini Nurmenniemi, Sara Bravaccini, Francesca Pirini, Sara Ravaioli, Arja Jukkola, Katri S. Selander. Human papillomavirus protein E6 regulates Toll like receptor-9 expression in breast cancer cells [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-26-04.

Critical Residues Involved in the Coassembly of L1 and L2 Capsid Proteins of Human Papillomavirus 16.

Human papillomaviruses (HPV) are small DNA viruses associated with cervical cancer, warts, and other epithelial tumors. Structural studies have shown that the HPV capsid consists of 360 copies of the major capsid protein, L1, arranged as 72 pentamers in a T=7 icosahedral lattice, coassembling with substoichiometric amounts of the minor capsid protein, L2. However, the residues involved in the coassembly of L1 and L2 remain undefined due to the lack of structure information. Here, we investigated the solvent accessibility surfaces (SASs) of the central cavity residues of the HPV16 L1 pentamer in the crystal structure because those internal exposed residues might mediate the association with L2. Twenty residues in L1 protein were selected to be analyzed, with four residues in the lumen of the L1 pentamer identified as important: F256, R315, Q317, and T340. Mutations to these four residues reduced the PsV (pseudovirus) infection capacity in 293FT cells, and mutations to R315, Q317, and T340 substantially perturb L2 from coassembling into L1 capsid. Compared with wild-type (WT) PsVs, these mutant PsVs also have a reduced ability to become internalized into host cells. Finally, we identified a stretch of negatively charged residues on L2 (amino acids [aa] 337 to 340 [EEIE]), mutations to which completely abrogate L2 assembly into L1 capsid and subsequently impair the endocytosis and infectivity of HPV16 PsVs. These findings shed light on the elusive coassembly between HPV L1 and L2. IMPORTANCE Over 200 types of HPV have been isolated, with several high-risk types correlated with the occurrence of cervical cancer. The HPV major capsid protein, L1, assembles into a T=7 icosahedral viral shell, and associates with the minor capsid protein, L2, which plays a critical role in the HPV life cycle. Despite the important role of the L2 protein, its structure and coassembly with L1 remain elusive. In this study, we analyzed the amino acid residues at the proposed interface between L1 and L2. Certain mutations at these sites decreased the amount of L2 protein assembled into the capsid, which, in turn, led to a decrease in viral infectivity. Knowledge about these residues and the coassembly of L1 and L2 could help to expand our understanding of HPV biology and aid in the development of countermeasures against a wide range of HPV types by targeting the L2 protein.

Past pregnancy, medical history, and sociodemographics are predictive of HPV vaccination status

The quadrivalent human papilloma virus (HPV) protein sub-unit vaccine nearly abolishes cervical cancer risk by preventing persistent infection with oncogenic subtypes of HPV. Unfortunately, HPV vaccination rates remain lower than anticipated. We aimed to study this trend within our region to identify what patient-specific factors influence HPV vaccination status.

Alteration of the IFN-Pathway by Human Papillomavirus Proteins: Antiviral Immune Response Evasion Mechanism.

A persistent infection with the so-called high-risk Human Papillomaviruses (hr-HPVs) plays a fundamental role in the development of different neoplasms. The expression of the HPV proteins throughout the different steps of the viral life cycle produce a disruption of several cellular processes, including immune response, which can lead to cell transformation. The interferon-mediated response plays an important role in eliminating HPV-infected and -transformed cells. The ability of HPV to disrupt the proper function of the interferon response is based on a series of molecular mechanisms coordinated by HPV proteins intended to prevent clearance of infection, ultimately producing an immunotolerant environment that facilitates the establishment of persistence and cancer. In this review, we focus on the molecular actions performed by HPV E1, E2, E5, E6 and E7 proteins on IFN signaling elements and their contribution to the establishment of infection, viral persistence and the progression to cancer.

Potential role of human papillomavirus proteins associated with the development of cancer.

Papillomaviruses are viruses with double-stranded DNA that are epitheliotropic and non-enveloped that infects cutaneous epithelial and mucosal cells in a species-specific way in several higher vertebrate species and cause cellular growth."There are around 100 different human papillomaviruses (HPVs)", as "more than 150 HPV types have been isolated and fully sequenced". We classify the probability of cancer development following viral infection with each HPV genotype into two types: "low-risk" and "high-risk." As a result, HPV diagnosis is a critical component of HPV genotype identification and characterization. Based on its activities, we may classify the HPV genome into three regions: the long control region (LCR) or the non-coding upstream regulatory region (URR), the late (L) region, and the early (E) region. Functional proteins are mostly static things that are not inflexible; they have undergone both local and global movements at various times and time ranges. The structural differences between HPV16 and 18 discovered by molecular modeling of the E6 oncoprotein were associated with their carcinogenic characteristics. Similarly, the E6 protein has two sets of C-X-X-C motifs that play significant roles in transformation, transcriptional activation, interactions, and immortalization with other proteins of cells in the host environment. Here, we review the literature regarding the protein mechanisms associated with HPV and how they cause cancer. Unless otherwise noted, it described all protein activities in terms of HPV proteins. The term "papillomaviruses" refers to groups of papillomavirus proteins that have a characteristic in common. HPV proteins can study the genetic influences on pathogenicity and the therapeutic applications of genomics. The future study provides a potential advancement in HPV infections and malignant illnesses to improve preventive and treatment strategies. Patients have been able to conquer this condition using a range of therapies and vaccines that were projected to be effective and robust enough to put an end to the ailment completely. In cancer prevention strategies, HPV vaccination is one of the most effective. It is safe, efficient, and long-lasting.

Marine derivatives prevent E6 protein of HPV: An in silico study for drug development

Cervical cancer (CC) is one of the most common cancers in women worldwide in which most cases are diagnosed with the Human Papilloma Virus (HPV). At the present time, there is neither a vaccine nor a drug to prevent or to effectively treat HPV infection. In the recent decades, compounds originated from marine organisms are well known for their novel chemical structures and wide range of biological activities. In the frame of our ongoing program to identify natural compounds endowed with anticancer bioactivities, this study conducted in silico assessment of 502 compounds originated from marine organisms against E6 protein of HPV for potential inhibition activity. The tertiary structure of targeted protein was constructed using SWISS-MODEL in which obtained Ramachandran plot proved the high quality of the protein model with 87.7% residues located in the most favored region and 11.6% residues allocated in the allowed region. All studied compounds were evaluated for drug-like and pharmacokinetic properties. AutoDock 4.2.6 and AutoDock Vina 1.2.0 were utilized to investigate the docking conformation of studied compounds towards E6 protein. High correlation coefficient between the dock score of AutoDock 4.2.6 and AutoDock Vina 1.2.0 was recorded with the value of R = 0.62. Docking outcomes in combination with ADMET studies identified compounds 153, 185 and 500 are the top “hits” for further drug development based on dock score ranking and docking conformation analysis, in particularly, compound 153 could be considered with caution due to its potent in causing mutation.

P53 Polymorphism in Oral Lichen Planus

Oral lichen planus (OLP) is a chronic relapsing inflammatory disease. It involves T-lymphocyte aggression targeted to the basal layer of the oral mucosa.p53 plays a central role in the prevention of normal cells from the development of the malignant phenotype. Somatic alterations in p53 cause defects in normal p53 function. Wild type p53 plays an important role in repairable damage of the cell due to cellular stresses. Over-expression, as well as polymorphic variants of Mouse double minute 2(MDM2), have effects on p53 disturbances. In addition, degradation of p53 by E6 protein of high-risk human papillomavirus is also suggested as one of the mechanisms which attenuate p53 responses in oral carcinogenesis. Polymorphisms in p53 are anticipated to cause measurable disturbance in p53 function. Polymorphism of the codon 72 on exon 4 of the gene p53 is the first and most commonly known polymorphism of this gene. The presence of p53 has been demonstrated as an early marker of dysplasia in Oral Potentially Malignant Disorders. This review discusses about p53 polymorphism as an early indicator of genetic predisposition to neoplastic transformation in OLP.