A Novel Mutant of Human Papillomavirus Type 18 E6E7 Fusion Gene and its Transforming Activity

Zhou, Zhixiang; Zhao, Chen; Li, Qianqian; Zeng, Yi

doi:10.7314/apjcp.2014.15.17.7395

Cited by 3 publications

(3 citation statements)

References 12 publications

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“…The stop codon is removed from E7 to permit fusion with HPV18 E7. A parallel set of inactivating mutations have also been introduced into HPV18 E7 (detox), specifically, C27G (62), E29G (16), and C98G (63), and the stop codon was removed from HPV18 E7 to permit fusion with HPV16 E6. The HPV16 E6(detox) gene contains multiple mutations to disrupt oncogenic activity by targeting key cysteine residues in the two zinc finger domains via C63G and C106G mutations.…”

Section: Methodsmentioning

confidence: 99%

Development of DNA Vaccine Targeting E6 and E7 Proteins of Human Papillomavirus 16 (HPV16) and HPV18 for Immunotherapy in Combination with Recombinant Vaccinia Boost and PD-1 Antibody

Peng

Gaillard

Wang

et al. 2021

mBio

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Immunotherapy for cervical cancer should target high-risk human papillomavirus types 16 and 18, which cause 50% and 20% of cervical cancers, respectively. Here, we describe the construction and characterization of the pBI-11 DNA vaccine via the addition of codon-optimized human papillomavirus 18 (HPV18) E7 and HPV16 and 18 E6 genes to the HPV16 E7-targeted DNA vaccine pNGVL4a-SigE7(detox)HSP70 (DNA vaccine pBI-1). Codon optimization of the HPV16/18 E6/E7 genes in pBI-11 improved fusion protein expression compared to that in DNA vaccine pBI-10.1 that utilized the native viral sequences fused 3′ to a signal sequence and 5′ to the HSP70 gene of Mycobacterium tuberculosis. Intramuscular vaccination of mice with pBI-11 DNA better induced HPV antigen-specific CD8+ T cell immune responses than pBI-10.1 DNA. Furthermore, intramuscular vaccination with pBI-11 DNA generated stronger therapeutic responses for C57BL/6 mice bearing HPV16 E6/E7-expressing TC-1 tumors. The HPV16/18 antigen-specific T cell-mediated immune responses generated by pBI-11 DNA vaccination were further enhanced by boosting with tissue-antigen HPV vaccine (TA-HPV). Combination of the pBI-11 DNA and TA-HPV boost vaccination with PD-1 antibody blockade significantly improved the control of TC-1 tumors and extended the survival of the mice. Finally, repeat vaccination with clinical-grade pBI-11 with or without clinical-grade TA-HPV was well tolerated in vaccinated mice. These preclinical studies suggest that the pBI-11 DNA vaccine may be used with TA-HPV in a heterologous prime-boost strategy to enhance HPV 16/18 E6/E7-specific CD8+ T cell responses, either alone or in combination with immune checkpoint blockade, to control HPV16/18-associated tumors. Our data serve as an important foundation for future clinical translation. IMPORTANCE Persistent expression of high-risk human papillomavirus (HPV) E6 and E7 is an obligate driver for several human malignancies, including cervical cancer, wherein HPV16 and HPV18 are the most common types. PD-1 antibody immunotherapy helps a subset of cervical cancer patients, and its efficacy might be improved by combination with active vaccination against E6 and/or E7. For patients with HPV16+ cervical intraepithelial neoplasia grade 2/3 (CIN2/3), the precursor of cervical cancer, intramuscular vaccination with a DNA vaccine targeting HPV16 E7 and then a recombinant vaccinia virus expressing HPV16/18 E6-E7 fusion proteins (TA-HPV) was safe, and half of the patients cleared their lesions in a small study (NCT00788164). Here, we sought to improve upon this therapeutic approach by developing a new DNA vaccine that targets E6 and E7 of HPV16 and HPV18 for administration prior to a TA-HPV booster vaccination and for application against cervical cancer in combination with a PD-1-blocking antibody.

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Section: Methodsmentioning

confidence: 99%

Development of DNA Vaccine Targeting E6 and E7 Proteins of Human Papillomavirus 16 (HPV16) and HPV18 for Immunotherapy in Combination with Recombinant Vaccinia Boost and PD-1 Antibody

Peng

Gaillard

Wang

et al. 2021

mBio

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“…E6 and E7 are the major oncoproteins of high-risk HPVs (Nakagawa et al, 1995;Zhou et al, 2014). Since E6 and E7 are consistently expressed in most cervical cancers and their precursor lesions but do not exist in normal tissues, these oncoproteins are targets for therapeutic vaccines that are presently in development, administering E6/E7 either in live vectors, as peptides, protein or nucleic acid form, or in cell-based vaccines (Seo et al, 2009;Yan et al, 2009;Wu et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Immunotherapeutic Effects of Dendritic Cells Pulsed with a Coden-optimized HPV 16 E6 and E7 Fusion Gene in Vivo and in Vitro

Zhou¹,

Li²,

Guan³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Background: : Cervical cancer is the second most common cause of cancer related death of women. Persistent HPV infection, especially with high-risk types such as HPV16 and HPV18, has been identified to be the primary cause of cervical cancer. E6 and E7 are the major oncoproteins of high-risk HPVs, which are expressed exclusively in HPV infected tissues, and thereby represent ideal therapeutic targets for immunotherapy of cervical cancer. Materials and Methods: In this work, we used recombinant adenovirus expressing coden-optimized HPV16 E6 and E7 fusion protein (Ad-ofE6E7) to prime dendritic cells (DC-ofE6E7), to investigate the ability of primed DC vaccine in eliciting antitumor immunity in vitro and vivo. Results: Our results indicated that DC-ofE6E7 vaccine co-culturing with splenocytes could strongly induce a tumor-specific cytotoxic T lymphocyte (CTL) response and kill the TC-1 cells effectively in vitro. Moreover, DC-ofE6E7 vaccine induced protective immunity against the challenge of TC-1 cancer cells in vivo. Conclusions: The results suggested that the HPV16 ofE6E7 primed DC vaccine has potential application for cervical cancer immunotherapy.

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“…In recent decades, the works of our laboratory and other international laboratories have shown that HPV is also an important cause of esophageal cancer (4)(5)(6)(7)(8)(9)(10)(11)(12). More than 80% of esophageal cancer patients in China's Shantou area are concomitant with HPV 16 and 18 infections.…”

Section: Original Articlementioning

confidence: 99%

A transcriptomic analysis of malignant transformation of human embryonic esophageal epithelial cells by HPV18 E6E7

Tang¹,

Wang²,

Khodahemmati³

et al. 2020

Transl Cancer Res TCR

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Background: Esophageal cancer is one of the most common malignant tumours in humans. A series of esophageal cancer cell lines are accompanied by human papilloma virus (HPV) infection, but the mechanism behind HPV in cancer malignancy is not clear.Methods: This research was conducted in different generations of HPV E6E7 gene-induced human foetal esophageal epithelial immortalised cells (Shantou Human Embryonic Esophageal Epithelial cell line; SHEE); the RNA sequencing transcriptomic analysis was performed to explore the mechanism of HPV infection in these cell lines. Results:The results showed that there are 9,990 differential genes in late-stage cells compared with HPV18 E6E7-infected early foetal esophageal epithelial immortalised cells. Among these, 4,882 genes are upregulated, and 5,108 genes are downregulated. We used bioinformatics to analyze the expression and function of aberrantly expressed lncRNA, miRNA, mRNA and construct the competing endogenous RNA (ceRNA) network and protein protein interaction (PPI) network.Conclusions: we predicted TP53TG1 promotes to malignant transformation of SHEEs by acting as a ceRNA to competitively bind to miR-6835 and regulate IGF2 expression. We also predicted IL6 serve as prognostic biomarkers and therapy target. With these results maybe provides new insights into the mechanisms of HPV carcinogenesis in esophageal cancer.

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A Novel Mutant of Human Papillomavirus Type 18 E6E7 Fusion Gene and its Transforming Activity

Cited by 3 publications

References 12 publications

Development of DNA Vaccine Targeting E6 and E7 Proteins of Human Papillomavirus 16 (HPV16) and HPV18 for Immunotherapy in Combination with Recombinant Vaccinia Boost and PD-1 Antibody

Development of DNA Vaccine Targeting E6 and E7 Proteins of Human Papillomavirus 16 (HPV16) and HPV18 for Immunotherapy in Combination with Recombinant Vaccinia Boost and PD-1 Antibody

Immunotherapeutic Effects of Dendritic Cells Pulsed with a Coden-optimized HPV 16 E6 and E7 Fusion Gene in Vivo and in Vitro

A transcriptomic analysis of malignant transformation of human embryonic esophageal epithelial cells by HPV18 E6E7

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