Development of a Spontaneous HPV16 E6/E7-Expressing Head and Neck Squamous Cell Carcinoma in HLA-A2 Transgenic Mice

Our data indicate that mutated HPV16 E6(R55K)(delK75) and mutated HPV16 E7(N53S) DNA abolishes the presentation of HPV16 E6 and E7 through murine MHC-I and results in their presentation through human HLA-A2 molecules. Additionally, the mutated HPV16 E6 and E7 remain oncogenic.

The Efficacy of Therapeutic DNA Vaccines Expressing the Human Papillomavirus E6 and E7 Oncoproteins for Treatment of Cervical Cancer: Systematic Review

Cervical cancer is recognized as a serious public health problem since it remains one of the most common cancers with a high mortality rate among women despite existing preventative, screening, and treatment approaches. Since Human Papillomavirus (HPV) was recognized as the causative agent, the preventative HPV vaccines have made great progress over the last few years. However, people already infected with the virus require an effective treatment that would ensure long-term survival and a cure. Currently, clinical trials investigating HPV therapeutic vaccines show a promising vaccine-induced T-cell mediated immune response, resulting in cervical lesion regression and viral eradication. Among existing vaccine types (live vector, protein-based, nucleic acid-based, etc.), deoxyribonucleic acid (DNA) therapeutic vaccines are the focus of the study, since they are safe, cost-efficient, thermostable, easily produced in high purity and distributed. The aim of this study is to assess and compare existing DNA therapeutic vaccines in phase I and II trials, expressing HPV E6 and E7 oncoproteins for the prospective treatment of cervical cancer based on clinical efficacy, immunogenicity, viral clearance, and side effects. Five different DNA therapeutic vaccines (GX-188E, VGX-3100, pNGVL4a-CRT/E7(detox), pNGVL4a-Sig/E7(detox)/HSP70, MEDI0457) were well-tolerated and clinically effective. Clinical implementation of DNA therapeutic vaccines into treatment regimen as a sole approach or in combination with conservative treatment holds great potential for effective cancer treatment.

Prediction of Human proteins having interactions with HPV16 proteins using virus and host sequence motifs.

Background: Human Papillomavirus (HPV) infection has been found to be the major cause of cancer of cervical region, in females. Genome of HPV codes for 6 functional proteins E1, E2, E4, E5, E6 and E7. These proteins play different roles in development of HPV infection and its progression towards cervical cancer. The interactions of HPV proteins with human DNA and proteins occurs in the presence of short linear peptide motifs on these proteins, have similar sequence to those found on proteins in human cells. Methods: After identification of human motifs in HPV proteins, by use of ELM resource, their counter domains were found from PROSITE. The proteins of human proteome containing these counter domains were predicted as the proteins having possibility of interactions with HPV proteins. Results: we predicted 9468 human proteins for having interactions with HPV proteins. Our predicted proteins were enriched with the host proteins having possibility of being interacted by HPV proteins. 10% of our predicted proteins were already reported to be affected by one or more HPV proteins. The list of predicated proteins can be utilized to find out the connectivity between the virus HPV and human host. It can also be used to determine the pathways involved in pathogenesis of HPV leading towards the cervical cancer Conclusion: The list of predicated proteins can be utilized to find out the connectivity between the virus HPV and human host. It can also be used to determine the pathways involved in pathogenesis of HPV leading towards the cervical cancer.

Diverse tumorigenic consequences of human papillomavirus integration in primary oropharyngeal cancers

Human papillomavirus (HPV) causes 5% of all cancers and frequently integrates into host chromosomes. The HPV oncoproteins E6 and E7 are necessary but insufficient for cancer formation, indicating that additional secondary genetic events are required. Here, we investigate potential oncogenic impacts of virus integration. Analysis of 105 HPV-positive oropharyngeal cancers by whole-genome sequencing detects virus integration in 77%, revealing five statistically significant sites of recurrent integration near genes that regulate epithelial stem cell maintenance (i.e., SOX2, TP63, FGFR, MYC) and immune evasion (i.e., CD274). Genomic copy number hyperamplification is enriched 16-fold near HPV integrants, and the extent of focal host genomic instability increases with their local density. The frequency of genes expressed at extreme outlier levels is increased 86-fold within ±150 kb of integrants. Across 95% of tumors with integration, host gene transcription is disrupted via intragenic integrants, chimeric transcription, outlier expression, gene breaking, and/or de novo expression of noncoding or imprinted genes. We conclude that virus integration can contribute to carcinogenesis in a large majority of HPV-positive oropharyngeal cancers by inducing extensive disruption of host genome structure and gene expression.

Genetic Variability and Phylogeny of Human Papillomavirus Type 16 Based On E6, E7 and L1 Genes in Central China

In the current study, a total of 74 single-infected HPV16 samples from females attending the gynecological outpatient clinic in four cities of Henan province were collected and applied to the L1, E6 and E7 sequencing. Variations of the HPV16 L1, E6 and E7 genes were characterized by comparison with reference sequence and the secondary structure analysis were conducted. Phylogenetic trees based on the L1 and E6-E7 sequences were constructed separately. B-cell epitopes of the HPV16 E6 and E7 proteins were predicted further. A total of thirty-seven novel variations, including twenty L1 genes and seventeen E6-E7 genes were identified. Compared with the reference sequence, twenty-eight variations (1.8%, 28/1596) were identified in L1 gene sequences and 10/28 (35.7%) were non-synonymous mutations. For E6-E7 sequences, twenty-five novel gene changes (including 16 mutations (3.4%, 16/477) in E6 gene, 9 mutations (3.0%, 9/297) in E7 gene) were found, 18/25 (72.0%) were non-synonymous and 10/28 (35.7%) were non-synonymous mutations. Phylogenetic analysis showed that 56.8% (42/74) of the samples were A1 sublineages, 37.8% (28/74) were A4, 4.1% (3/74) were A3 and 1.4% (1/74) was A2 sublineages. On the prediction of B-cell epitopes, seven potent epitopes for E6 and four for E7 were identified. Amino mutations, including L90V, R62K, R142Q and F76L in E6, S63F and N29S/H in E7 changed the score. HPV16 variants prevalent in the central China belong to European A1 sublineages. Sequences of HPV16 L1, E6 and E7 in this study may provide assistant for the improvement of HPV vaccines.

Influenza virus vector iNS1 expressing bovine papillomavirus 1 (BPV1) antigens efficiently induces tumour regression in equine sarcoid patients

Bovine papillomaviruses types 1 and 2 (BPV1, BPV2) commonly induce skin tumours termed sarcoids in horses and other equids. Sarcoids seriously compromise the health and welfare of affected individuals due to their propensity to resist treatment and reoccur in a more severe form. We have developed influenza (Flu) A and B virus vectors that harbour a truncated NS1 gene (iNS) assuring interferon induction and co-express shuffled BPV1 E6 and E7 antigens for sarcoid immunotherapy. In a safety trial involving 12 healthy horses, intradermal administration of iNSA/E6E7equ and iNSB/E6E7equ was well tolerated, with the only transient side effect being mild fever in four horses. Repeated screening of secretions and faeces by RT-PCR and plaque assay revealed no virus shedding, thus also confirming biological safety. In a patient trial involving 29 horses bearing BPV1-induced single or multiple sarcoids, at least one lesion per horse was intratumourally injected and then boosted with iNSA/E6E7equ and/or iNSB/E6E7equ. The treatment induced a systemic antitumour response as reflected by the synchronous regression of injected and non-injected lesions. Irrespective of vaccination schemes, complete tumour regression was achieved in 10/29 horses. In 10/29 horses, regression is still ongoing (May 2021). Intriguingly, scrapings collected from former tumour sites in two patients tested negative by BPV1 PCR. Nine severely affected individuals with a history of unsuccessful therapeutic attempts did not (6/29) or only transiently (3/29) respond to the treatment. INSA/E6E7equ and iNSB/E6E7equ proved safe and effective in significantly reducing the tumour burden even in severe cases.

Human Papillomavirus (HPV)

HPV is extremely common worldwide and mainly transmitted through sexual contact; most people are infected with HPV shortly after onset of sexual activity. There are >200 types of HPV, of which at least 12 are cancer-causing (oncogenic or high-risk types). HPV is a causal factor for several anogenital and a subset of oropharyngeal cancers with 2 HPV types (16 and 18) causing 72% of all HPV-associated cancers. Cervical cancer is the fourth most common cancer among women globally with nearly 90% of the deaths occurring in low- and middle-income countries. Comprehensive cervical cancer control includes primary prevention (vaccination against HPV), secondary prevention (screening and treatment of pre-cancerous lesions) as well as treatment of invasive cervical cancer. The currently licensed vaccines are L1 VLP-based and prophylactic; they have been shown to be safe and highly effective in preventing HPV infections and HPV-associated lesions, precancer and cancer. Neutralizing antibodies are the mechanism of protection for prophylactic HPV VLP-based vaccines. Therapeutic HPV vaccines targeting the oncoproteins E6 and E7 are in clinical development.

Human Papillomaviruses-Associated Cancers: An Update of Current Knowledge

Human papillomaviruses (HPVs), which are small, double-stranded, circular DNA viruses infecting human epithelial cells, are associated with various benign and malignant lesions of mucosa and skin. Intensive research on the oncogenic potential of HPVs started in the 1970s and spread across Europe, including Croatia, and worldwide. Nowadays, the causative role of a subset of oncogenic or high-risk (HR) HPV types, led by HPV-16 and HPV-18, of different anogenital and head and neck cancers is well accepted. Two major viral oncoproteins, E6 and E7, are directly involved in the development of HPV-related malignancies by targeting synergistically various cellular pathways involved in the regulation of cell cycle control, apoptosis, and cell polarity control networks as well as host immune response. This review is aimed at describing the key elements in HPV-related carcinogenesis and the advances in cancer prevention with reference to past and on-going research in Croatia.

Corrigendum

Minor changes are required in the Funding information and the acknowledgement for the article entitled “Organosulphur Compounds Induce Apoptosis and Cell Cycle Arrest in Cervical Cancer Cells via Downregulation of HPV E6 and E7 Oncogenes” in “Anti-Cancer Agents in Medicinal Chemistry, 2021, Vol. 21, No. 3, pp. 393-405.” The correct Funding information and Acknowledgement is given below: FUNDING: This project was funded by the Council of Science and Technology (CST), Lucknow, Uttar Pradesh, India (Sanction No. CST/374). The financial support during this research was also provided by the Deanship of Scientific Research, King Khalid University, Abha, Saudia Arabia through the General Research Project under grant number R.G.P. 01/48/42. ACKNOWLEDGEMENT: IAA is greatly thankful to the Council of Science and Technology (CST), Uttar Pradesh, India, for providing him project as a Principal Investigator. Authors would also like to acknowledge the support of the King Khalid University through the General Research Project under grant number R.G.P. 01/48/42. under the Deanship of Scientific Research, King Khalid University, Abha, Saudia Arabia

Novel Antigenic Targets of HPV Therapeutic Vaccines

Human papillomavirus (HPV) infection is the cause of the majority of cervical cancers and head and neck cancers worldwide. Although prophylactic vaccines and cervical cancer screening programs have shown efficacy in preventing HPV-associated cervical cancer, cervical cancer is still a major cause of morbidity and mortality, especially in third world countries. Furthermore, head and neck cancer cases caused by HPV infection and associated mortality are increasing. The need for better therapy is clear, and therapeutic vaccination generating cytotoxic T cells against HPV proteins is a promising strategy. This review covers the current scene of HPV therapeutic vaccines in clinical development and discusses relevant considerations for the design of future HPV therapeutic vaccines and clinical trials, such as HPV protein expression patterns, immunogenicity, and exhaustion in relation to the different stages and types of HPV-associated lesions and cancers. Ultimately, while the majority of the HPV therapeutic vaccines currently in clinical testing target the two HPV oncoproteins E6 and E7, we suggest that there is a need to include more HPV antigens in future HPV therapeutic vaccines to increase efficacy and find that especially E1 and E2 could be promising novel targets.