Human papillomavirus infection mechanism and vaccine of vulva carcinoma

Qing Tong; Lingqi Zheng; Ruiying Zhao; Tianling Xing; Yunbo Li; Tong Lin; Xuan Zhang; Zhe Jin

doi:10.1515/biol-2016-0024

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Human papillomavirus infection mechanism and vaccine of vulva carcinoma

Qing Tong , Lingqi Zheng , Ruiying Zhao , Tianling Xing , Yunbo Li , Tong Lin , Xuan Zhang und Zhe Jin

Veröffentlicht/Copyright: 8. September 2016

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Abstract

Vulvar carcinoma is a rare tumor occurring in female patients. Though more than 40% of vulva cancers are due to the infection of human papillomavirus (HPV), understanding of HPV and vulvar carcinoma is insufficient. HPV expression is regulated by cellular and viral transcription factors that bind to specific elements within the ligase chain reaction. These proteins bind with different affinity to host cell proteins and disrupt normal epithelial differentiation and apoptosis. Immunotherapy does not target tumors, but instead targets the host immune system. Active immunotherapy is tumor-targeting or immune-targeting monoclonal antibodies and vaccines. Nonspecific active immunotherapy is mainly cytokine therapy. In the treatment and prevention of HPV, the most popular research projects were regarding peptide, recombinant protein and DNA-based vaccines, recombinant virus and other targets in HPV infection. Since the cervix and vulva are both susceptible areas, these studies may be able to help reduce prevalence of vulvar precancerous lesions and prevent all cancers caused by HPV.

Keywords: Human papillomavirus; Vulva carcinoma; Infection mechanism; Vaccine; Immune-targeting therapy

1 Background

Vulvar carcinoma is a rare tumor seen in female patients. It is the fourth most common gynecologic cancer after cancer of the uterine corpus, ovary, and cervix, and constitutes 5% of all malignancies of the female genital tract [1]. The prognosis is good if vulvar cancer is diagnosed at an early stage and the treatment is correct. In recent years, people have taken more and more interest in the precancerous lesions of vulva.

There are several histological types of vulvar carcinoma. Squamous cell carcinoma of the vulva is the most common malignant tumor which takes place in nearly 95% of vulvar carcinomas, followed by melanoma, sarcoma, and basalioma [2]. Among those types, they all have similar causes but different characteristics and manifestations.

According to predisposing factors, vulvar cancer can be classified into two kinds: the first type occurs mostly in younger patients and correlates with human papillomavirus (HPV) infection. The second group occurs often in elderly women without neoplastic epithelial disorders and is not HPV associated.

Just as Annual Report to the Nation on the Status of Cancer, 2013 [3] reported, a large amount of cancers are due to the infection of HPV, including nearly all cervical cancers, 90% of anal cancers, more than 60% of certain subsites of oropharyngeal cancers, and 40% of vagina, vulva, and penile cancers. It has been estimated that HPV infection is the causative agent in approximately 43% of vulvar cancers worldwide [4]. HPV infection is also becoming one of the world’s most common sexually transmitted infections.

2 HPV

The Papillomaviridae family is a diverse group of small non-enveloped viruses. They infect the mucosal and cutaneous epithelia of a broad variety of highervertebrates in a species-specific way, mostly through minor wounds or infected areas. At the time of writing, over 150 different HPV genotypes have been fully sequenced and numbered in the order of their discovery [5]. More than 100 types have been confirmed in the disease, of which high-risk types (such as HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 73, and 82) are associated with carcinogenesis and most common or undifferentiated types (such as HPV 6, 7, 11, 42, 43, 70, and 90) related to benign lesions like anogenital warts. The five most prevalent types worldwide are HPV 16 (3.2%), HPV 18 (1.4%), HPV 52 (0.9%), HPV 31 (0.8%) and HPV 58 (0.7%) [6]. HPV 16 and 18 are the most common HPV types, and are found in nearly 70% of cervical cancers in all of those oncogenic HPV types. HPV 16 is detected in 75% of high-grade vulvar intra-epithelial neoplasia (VIN). HPV 16 and 18 combined infections account for 93% of HPV-associated vulvar cancers [7].

HPV is one of the most common sexually transmitted infections. It is the cause of a large number of neoplasias, including cervical, anal, vulvar, vaginal, penile, and oropharyngeal cancers. HPV presents specificity for different tissues and different anatomical sites. The majority of HPV genotypes belong to different genera named after the Greek alphabet α, β, γ, μ and ν [8]. Only α-papillomavirus is isolated from genital lesions. Though HPV infections are usually transient and even those that persist for a few months are usually cleared naturally without any symptoms, it is not a specific cause of vulvar carcinoma, but it is the most direct cause of it. Furthermore, women with persistant infection of oncogenic HPV are more likely to have VIN and vulvar carcinoma [9]. Numerous determinants are participate in the progression of HPV infection, such as VIN, including behavioral determinants such as sexual intercourse with increasing numbers of sexual partners [10], contraceptive use [11], previous pregnancy and delivery, tobacco exposure [12] and infections of other sexually-transmitted pathogens [13] like herpes simplex virus (HSV). Also, viral factors including genotype, variants, viral load and viral integration will have an influence [14]. In older women, especially post-menopausal women, cancer in vulvar skin are mostly affected by squamous hyperplasia or lichen sclerosus which is associated with malignancy and hyperplasia. That may be due to the immunosuppression or nutritional deficiency of the vulva. Also, obesity, hypertension, diabetes mellitus and metabolic syndrome (MetS) [15] may have an influence, but are not independent risk factors of vulvar cancer.

3 Mechanism

3.1 Influence on cell cycle

The HPV virion is approximately 55–60 nm in diameter [16]. It is a single-closed circular double-stranded DNA genome of about 8,000 base pairs that encodes the Upstream Regulatory Region (URR), early proteins E1, E2, E4, E5, E6, E7, and late proteins L1 and L2 [17]. Its DNA genome is enclosed by cellular histones comprise of an icosahedral capsid without any envelope outside.

HPVs invade the undifferentiated proliferative basal cells of the epithelial mucosa which are exposed by tissue trauma. HPV creates productive infections within the stratified epithelia. In this way, the viral reproduction is closely linked to the differentiation program of the infected epithelial cell. HPV expression is regulated by cellular and viral transcription factors that bind to specific elements within the ligase chain reaction (LCR), which varies widely in different HPV types using the cellular nutrition, ATP and organelles as its feedstock. According to the research by Longworth MS and Laimins LA, the E6 and E7 cooperate in the immortalization of primary human keratinocytes and in the inhibition of the differentiation of these cells induced. The protein E6 relate to the inactivation of p53 as the protein E7 could change the host cell cycle through the combination with retinoblastoma tumor suppressor protein (pRB) [18,19].

These proteins bind with different affinity to host cell proteins and disturb the normal epithelial differentiation and apoptosis. They stimulate the infected physiological functions of cellular proliferation by reentering the S phase in the viral life cycle and facilitating the stable maintenance of episomes. As origin recognition factors, the E1 and E2 proteins can regulate early viral transcription [20]. The functions of the E3-E4 proteins are still unknown, but it can be confirmed that these proteins have been implicated in modulating late viral functions. E5 is not highly conserved at the nucleotide level. It is tied with late gene viral life-cycle events and interacts with epidermal growth factor (EGF) and platelet derived growth factor (PDGF) to influence cellular proliferation. The E5 encodes for a transmembrane protein that probably contributes to cell signaling [21] and are thought to act by modulating the activity of cellular proteins [22]. The capsid of the virus consists of the main capsid protein L1 and the minor capsid protein L2. The protein L1 can assemble spontaneously into an icosahedral structure that closely resembles the virions themselves while protein L2 plays an essential role in viral DNA encapsidation and in the viral infectious entry channel to deliver the viral DNA into the host cell [23]. Both the L1 and L2 proteins are used to generate progeny virion for its own reproduction by participating in the self-assembly as a virus-like particle (VLP) [24].

The E2 early regulatory protein is determined by at least four different conserved sites in the LCR and inhibits E6 and E7 transcription. If the E2 gene is interrupted, it cannot lead to an elevated expression of the E6 and E7 oncogenes so that viral genomes are frequently integrated into the host DNA in tumor cells. Based on the identity of the infected epithelial cell type, transcription integrate the differentiation status of the stratified epithelium, and the episomal or chromosomal viral genome in a complex manner [25].

Some researchers found the association and degradation of TP53 and pRB by E6 and E7, respectively. TP53 mediates cell cycle arrest by blocking the progression at the G1/S checkpoint and E6-induced TP53 degradation abolishes this control [26]. At the same time, high-risk HPV E6 stimulates cell proliferation by interacting with PDZ proteins including MUPP-1, hSCRIB and hDlg [27], and increases the lifespan of infected cells through the activation of telomerase.

In UK women with HPV-associated vulval intraepithelial neoplasia and vulval squamous cell carcinoma, p53 codon 72 polymorphism were analyzed. They conclude that the arginine polymorphism may confer protection against the development of HPV-associated vulval neoplasia. The hypothesis that HPV positive VIN and VSCC were associated with being homozygous for the arginine variant was thereby tested [28].

3.2 Host immune response

Unlike other viruses, HPV does not kill the stratified epithelium cells. Instead, they reproduce in the infected basal cells located in the epithelial transformation zone. In this process, both inherent immunity and adaptive immunity are activated.

HPV can infect cells through damaged skin tissue. When the damage is deep enough and reaches the basement membrane [29], the virus can infect keratinocytes. In the immune response, keratinocytes play an important role which can express toll like receptors (TLR), participate in the innate immune response and recognize both endogenous and exogenous threats, specifically pathogen-associated molecular patterns (PAMP) and damage-associated molecular patterns (DAMP) like the double-stranded DNA HPV genome or the L1 and L2 capsid proteins [30]. In this process, TLRs are activated and can synthesize and release a variety of cytokines involved in immune regulation like IL-1, IL-6, IL-8, IL-10, TNF-α and IFN-β to activate natural killer (NK) cells [31]. The NK-activating receptors affect the cytolytic functionality. It elicits a proinflammatory expression profile which promotes innate immunity. The initial inflammatory response leads to infiltration of immune cells such as neutrophils, macrophages and lymphocytes.

HPV infections are influenced by host immune response. Successful adaptive immune responses are believed to be mediated by local T cell-mediated immunity which lead to the clearance of genital HPV infection.

Recent data have suggested that the progression of HPV pre-cancerous lesions depends on both the suppression of cellular immunity, driven by the Th1 response, and the development of the immunosuppressive T-reg profile for neoplastic progression [32].

Carcinogenesis is a complex multi-step process, not only because viral genes take various actions to transform a normal cell into a cancer cell, but also because epithelial tissue progresses through phases of being normal epithelium, intraepithelial neoplasia tissue when developing into cancer.

4 Vaccines

The immune system plays an important role in controlling the development of HPV associated cancer. Immunotherapy has begun to revolutionize cancer treatment by introducing therapies. Now, our treatment target is no longer the tumor but instead, the host immune system. It has changed treatment from conventional therapies such as chemotherapy and radiation therapy to immune-targeted agents.

Specifically, it contains three kinds of therapy. One of them is passive immunotherapy or cellular therapy, which is adaptive T cells or NK cells. Another one is active immunotherapy like tumor-targeting or immune-targeting monoclonal antibodies and vaccines. The other one is nonspecific active immunotherapy, mainly cytokine therapy [33].

In the treatment and prevention of HPV, vaccines are the most common strategy under investigation. After the registration of vaccines in 2006, many teams in many countries have devoted their efforts into making different vaccines based on several targets. At the time of writing, a large number of therapeutic vaccines are in clinical trials. Some of the cases have been reported and the data has been collected. Population-level vaccination programs of young pre-sexually active women have been introduced in developed countries [34]. Now preventive vaccination against high risk HPV types are widely used in these countries. However, they are not suitable for third world countries due to high cost and requirement for special preservation conditions, despite those countries suffering the most from HPV related disease.

Peptides are easy to produce and use, inexpensive and the safest ingredient in making a peptide-based vaccine. However, they are weakly immunogenic and need to be mixed with adjuvants such as cytokines, TLR ligands and chemokines to improve their recognition by the immune system. Because it imitates the immunogenic part of the virus that activates the antigen presentation, most of the peptide-based vaccines are designed to be mixed with various peptides. A humoral response is evoked primarily.

In a study of 20 patients with HPV 16-positive which are high-grade vulvar intraepithelial neoplasias, they were immunized with a mix of long peptides from the HPV 16 viral oncoproteins E6 and E7 in adjuvant. Five patients had complete regression, and HPV 16 was no longer detected in four of them [35]. These patients also presented an increased T cell response.

Another team developed a highly immunogenic synthetic long peptide (SLP) vaccine, currently (at the time of writing) in phase II trial. It consists of long overlapping peptides of the E6 and E7 oncogenic proteins of HPV 16, with an excellent treatment profile in animal models. As we know, oncoproteins E6 and E7 are tumor-specific targets for the adaptive immune system. The HPV 16-SLP vaccine was well tolerated and induced a broad IFN-γ associated T-cell response in patients with advanced or recurrent HPV 16-induced gynecological carcinoma but neither induced tumor regression nor prevented progressive disease. They plan to use this vaccine in combination with chemotherapy and immunomodulation [36].

Recombinant proteins are widely studied to make a vaccine with more potential epitopes of an antigen. Of course, they also present low immunogenicity and need to be mixed with adjuvants such as proteins. TA-CIN consist of E6, E7, and L2 from HPV 16 and HPV 18. 11vle7 is made of chimeric VLPs consisting of a carboxyl-terminally truncated HPV 16 L1 protein fused to the amino-terminal part of the HPV 16 E7 protein. SGN-00101 is a fusion protein consisting of a Hsp from Mycobacterium bovis and HPV 16 E7 protein.

Other than peptides, DNA-based vaccines use the plasmid DNA that codes for the corresponding viral proteins. In form of naked DNA or RNA replicon, the process is relatively inefficient but the prospects are wide. They also need immunogenic amplification to improve antigen expression and presentation in APCs. The pConE6E7, ZYC101a, Amolimogene, Sig-E7 (detox)-HSP70 are all this kind of DNA vaccine. Recently, three genome-wide association studies have identified the PSCA (prostate stem cell antigen) rs2294008 polymorphism associated with cervical cancer and HPV infections. They found the polymorphism correlated to the early-stage cancer [37].

E6 and E7 oncogenes of HPV degrading tumor suppressor proteins act through the ubiquitin proteasome system (UPS) [38]. This could also be used in the development of HPV vaccine.

A large number of therapeutic vaccines are now in clinical trials all over the world. In contrast to preventive vaccines, therapeutic ones target the oncogenetic proteins E6 and E7 which are continuously expressed in the cells throughout the HPV infection. Furthermore, the requirement of these genes in cellular transformations make them necessary for the virus.

There are other vaccines made from recombinant viruses and other targets in infections of HPV. However, most of the vaccines are said to prevent or cure cervical cancer [39].

5 Conclusion

Even though vulvar carcinoma is the fourth most common gynecologic cancer and it correlates with HPV infection mostly in young women, our understanding of HPV and vulvar carcinoma is insufficient. With HPV infections remaining an important public health issue, as the vaccine becomes more widely used in developed countries, therapeutic effects of HPV vaccine in the prevention and treatment of vulvar carcinoma is however rarely reported. Since the cervix and vulva are both susceptible areas, perhaps they can reduce the prevalence of precancerous lesions of vulva and prevent all the cancers caused by HPV.

Authors’ Contribution: Qing Tong and Lingqi Zheng are co-first author which contributed equally to this work. All authors read and approved the paper.

Conflict of Interest: The authors report no potential conflicts of interest in this work and have nothing to disclose.

^* Gynaecology Department, Dongfang Hospital of Beijing University of Chinese Medicine, No.6 Fangxingyuan 1st Block, Fengtai District, Beijing 100078, P.R. China

Acknowledgments

This work is supported by Beijing Municipal Science and Technology Commission of P.R. China (No.Z151100004015153).

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Received: 2016-4-28

Accepted: 2016-6-18

Published Online: 2016-9-8

Published in Print: 2016-1-1

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.