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Oncogenic Human Papillomaviruses

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Infectious Diseases".

Deadline for manuscript submissions: closed (15 October 2021) | Viewed by 31612

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Special Issue Editors

Prof. Dr. Aldo Venuti

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Guest Editor

HPV Unit-UOSD Tumor Immunology and Immunotherapy-IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
Interests: viral infections; HPV infection; cervical cancer; head and neck cancer; skin cancer; rare tumors; DNA vaccines; non-viral vectors; nucleic acid vectors; biopharmaceuticals; drug delivery systems; cancer therapy; molecular biology of DNA viruses
Special Issues, Collections and Topics in MDPI journals

Dr. Francesca Paolini

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Guest Editor

1. HPV Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
2. UOSD Tumor Immunol & Immunotherapy, IRCCS Regina Elena National Cancer Institute, Rome, Italy
Interests: human papillomaviruses (HPVs); cervical cancer; DNA vaccine; immunotherapy; RNA silencing; beta beta HPV; head and neck cancer; immunity persistence; cancer therapy; E7 oncoprotein

Special Issue Information

Dear Colleagues,

After the introduction of effective preventive HPV vaccines into clinical practice, the belief could have been generated in the scientific community that the HPV problem is now solved. Nothing could be more wrong. In fact, although the incidence of cervical cancer is decreasing, that of HPV-associated cancer in oropharynx is increasing, representing a significant public health problem for which to date we do not have a definitive therapeutic strategy. The recent WHO call for the elimination of cervical cancer through preventive vaccination and screening highlighted the need to continue to implement these cornerstones in the fight against HPV. Furthermore, even in the most optimistic hypothesis of optimal global vaccination coverage, millions of patients currently suffering from HPV will surely require new and more effective therapeutic interventions. Developing new therapies also requires the implementation of technologies and procedures (i.e., in silico) that can ensure the validation of discovered treatments prior their use in humans. Finally, other HPVs besides the already known “high risk” types (i.e., beta HPV) may play a role in carcinogenesis, with different molecular mechanisms that require further studies in order to evaluate a possible preventive and/or therapeutic intervention against them.

Recent “omics” technologies have given and will give a further contribution to the identification of the genetic and epigenetic alterations induced by HPV in the host cell as well as of the complex molecular networks activated by viral proteins.

We welcome the submission of research and review articles on the molecular mechanisms contributing to HPV-induced carcinogenesis to bring together expert opinion and new advances from across the field in a Special Issue. We welcome proposals covering any relevant clinical or translational topics, including epidemiology, immune responses, viral oncogenes in cell transformation, virus and host mutational profiles, methylation, miRNA expression profiles, and new therapies including vaccines against HPVs that are related to tumor pathologies of different anatomic localization (i.e., anogenital, oropharyngeal, cutaneous, conjunctival, and other localizations).

Prof. Dr. Aldo Venuti
Dr. Francesca Paolini
Guest Editors

Manuscript Submission Information

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Keywords

human papillomaviruses (HPVs)
epidemiology
immune responses
viral oncogenes
virus/host mutational profile
methylation
miRNA expression profile
new HPV therapies
therapeutic/preventive vaccines

Published Papers (10 papers)

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Research

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10 pages, 829 KiB

Open AccessArticle

Detection of Human Papillomavirus DNA in Paired Peripheral Blood and Cervix Samples in Patients with Cervical Lesions and Healthy Individuals

by Kamylla Conceição Gomes Nascimento, Élyda Gonçalves Lima, Zhilbelly Mota Nunes, Marconi Rêgo Barros Júnior, Marcus Vinícius de Aragão Batista, Antonio Roberto Lucena Araujo, Jacinto da Costa Silva Neto, Bárbara Simas Chagas, Ana Pavla Almeida Diniz Gurgel and Antonio Carlos de Freitas

J. Clin. Med. 2021, 10(21), 5209; https://doi.org/10.3390/jcm10215209 - 08 Nov 2021

Cited by 7 | Viewed by 1853

Abstract

This study evaluated the presence of Human Papillomavirus (HPV) DNA in the cervix and peripheral blood of women with cervical intraepithelial neoplasia (CIN I, II, and III) and healthy individuals. Overall, 139 paired peripheral blood and cervix samples of healthy women and women with CIN I, II, and III (n = 68) were tested for HPV DNA by using standard procedures. Polymerase chain reaction (PCR) sequencing determined HPV types. Quantification of HPV16 E6 and E2 genes was performed to determine viral load and physical state. HPV DNA was detected in the cervix (21.1% in healthy individuals; 48.8–55.5% in CIN patients), blood (46.4% in healthy individuals; 44.1–77.7% in CIN patients) and paired peripheral blood and cervix samples (24% in healthy individuals; 32.5–44.4% in CIN patients). The most frequent types found in the cervix were HPV16, 18, 31, 33, 58, and 70, while HPV16, 18, 33, 58, and 66 were the most frequent types found in the blood. HPV DNA in the cervix was associated with previous sexually transmitted infections (STIs) (p = 0.023; OR: 2.978; CI:1.34–7.821), HPV DNA in the blood (p = 0.000; OR: 8.283; CI:3.700–18.540), and cervical lesions (CIN I/II or III) (p = 0.007). Binomial logistic regression showed that HPV DNA in the blood (p = 0.000; OR: 9.324; CI:3.612–24.072) and cervical lesions (p = 0.011; OR: 3.622; CI:1.338–9.806) were associated with HPV DNA in the cervix. However, we did not find an association between HPV DNA in the blood and cervical lesions (p = 0.385). Our results showed that only HPV DNA found in the cervix was associated with cervical lesions. Full article

(This article belongs to the Special Issue Oncogenic Human Papillomaviruses)

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11 pages, 647 KiB

Open AccessArticle

Intra-Anal Imiquimod Cream against Human Papillomavirus Infection in Men Who Have Sex with Men Living with HIV: A Single-Arm, Open-Label Pilot Study

by Duygu Durukan, Tiffany R. Phillips, Gerald L. Murray, Jason J. Ong, Andrew E. Grulich, I. Mary Poynten, Fengyi Jin, Catriona S. Bradshaw, Ivette Aguirre, Julie Silvers, Helen Kent, Steph Atchison, Prisha Balgovind, Alyssa Cornall, Marcus Y. Chen, Christopher K. Fairley and Eric P. F. Chow

J. Clin. Med. 2021, 10(19), 4477; https://doi.org/10.3390/jcm10194477 - 28 Sep 2021

Viewed by 6679

Abstract

Men who have sex with men (MSM) living with HIV have a high prevalence and incidence of anal high-risk human papillomavirus (hrHPV) and anal cancer. We conducted an open-label, single-arm pilot study to examine the tolerability of imiquimod cream among MSM aged ≥18 years, living with HIV, who tested positive for anal hrHPV at Melbourne Sexual Health Centre between April 2018 and June 2020. We instructed men to apply 6.25 mg imiquimod intra-anally and peri-anally 3 doses per week for 16 weeks (period 1) and then one dose per week for a further 48 weeks (period 2). Twenty-seven MSM enrolled in period 1 and 24 (86%) applied at least 50% of doses. All men reported adverse events (AEs), including 39.5% grade 1, 39.5% grade 2, and 21% grade 3 AEs on at least one occasion. Eighteen MSM (67%) temporarily stopped using imiquimod during period 1, most commonly due to local AEs (n = 11) such as irritation and itching. Eighteen MSM continued in period 2 and all applied at least 50% of doses with no treatment-limiting AEs reported. Imiquimod 3 doses per week caused local AEs in most men and was not well tolerated. In contrast, once-a-week application was well tolerated over 48-weeks with no treatment-limiting AEs. Full article

(This article belongs to the Special Issue Oncogenic Human Papillomaviruses)

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14 pages, 1336 KiB

Open AccessArticle

Multiparametric MRI Evaluation of Oropharyngeal Squamous Cell Carcinoma. A Mono-Institutional Study

by Francesca Piludu, Simona Marzi, Emma Gangemi, Alessia Farneti, Laura Marucci, Aldo Venuti, Maria Benevolo, Barbara Pichi, Raul Pellini, Francesca Sperati, Renato Covello, Giuseppe Sanguineti and Antonello Vidiri

J. Clin. Med. 2021, 10(17), 3865; https://doi.org/10.3390/jcm10173865 - 28 Aug 2021

Cited by 6 | Viewed by 1814

Abstract

The aim of this paper is to define the pre-treatment radiological characteristics of oropharyngeal squamous cell carcinoma (OPSCC) using morphological and non-morphological magnetic resonance imaging (MRI), based on HPV status, in a single-institution cohort. In total, 100 patients affected by OPSCC were prospectively enrolled in the present study. All patients underwent 1.5T MR with standard sequences, including diffusion-weighted imaging with and intravoxel incoherent motion (IVIM-DWI) technique and a dynamic contrast-enhanced (DCE) MRI. For all patients, human papillomavirus (HPV) status was available. No statistically significant differences in the volume of primary tumors (PTs) and lymph nodes (LNs) were observed based on HPV status. When comparing the two patient groups, no significant differences were found for the PT radiologic characteristics (presence of well-defined borders, exophytic growth, ulceration, and necrosis) and LN morphology (solid/cystic/necrotic). Tumor subsite, smoking status, and alcohol intake significantly differed based on HPV status, as well as ADC and D_t values of both PTs and LNs. We detected no significant difference in DCE-MRI parameters by HPV status. Based on a multivariate logistic regression model, the combination of clinical factors, such as tumor subsite and alcohol habits, with the perfusion-free diffusion coefficient D_t of LNs, may help to accurately discriminate OPSCC by HPV status. Full article

(This article belongs to the Special Issue Oncogenic Human Papillomaviruses)

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12 pages, 381 KiB

Open AccessArticle

Prevalence of High-Risk Human Papillomavirus Infections before and after Cervical Lesion Treatment, among Women Living with HIV

by Timothée Dub, Sophie Le Cœur, Nicole Ngo-Giang-Huong, Wanmanee Matanasarawut, Pornnapa Suriyachai, Kannikar Saisawat, Chaiwat Putiyanun, Sudanee Buranabanjasatean, Prattana Leenasirimakul, Samreung Randaeng and Tristan Delory

J. Clin. Med. 2021, 10(14), 3133; https://doi.org/10.3390/jcm10143133 - 15 Jul 2021

Cited by 1 | Viewed by 2246

Abstract

Even when receiving combination antiretroviral therapy, women living with HIV are at high risk of human papillomavirus (HPV) infection and/or cervical lesions, including cancer. Using data from the PapilloV prospective cohort, we evaluated the prevalence of high-risk HPV (HR-HPV) infections after cervical lesion treatment and investigated factors associated with their carriage. Women were followed up for three years with annual Pap smear and HPV genotyping. We offered treatment to women presenting either a Pap smear with high-grade squamous intraepithelial lesion or higher, and/or a biopsy showing cervical intraepithelial neoplasia II or III. We compared the prevalence of HR-HPV infection at the time of first treatment indication and at the end of follow-up among women who received treatment and those who did not. Overall, 46 women had treatment indication. HR-HPV prevalence significantly decreased from 67% to 27% (p value = 0.001) in the 30 women who received treatment, while it did not significantly decrease (from 56% to 38%) in the 16 women who did not (p value = 0.257). Due to lack of statistical power, the 40% relative difference in HR-HPV carriage between treated and untreated women was not significant. In women living with HIV, the treatment of a cervical lesion may be beneficial for clearing HR-HPV infections. Full article

(This article belongs to the Special Issue Oncogenic Human Papillomaviruses)

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9 pages, 861 KiB

Open AccessArticle

Predictors of Oral Infection by Mucosal and Cutaneous Human Papillomaviruses in HIV-Infected and Uninfected Men Who Have Sex with Men of the OHMAR Study

by Massimo Giuliani, Tarik Gheit, Francesca Rollo, Massimo Tommasino, Alessandra Latini, Maria Benevolo, Barbara Pichi, Raul Pellini, Sandrine McKay-Chopin, Antonio Cristaudo, Eugenia Giuliani, Aldo Morrone and Maria Gabriella Donà

J. Clin. Med. 2021, 10(13), 2804; https://doi.org/10.3390/jcm10132804 - 25 Jun 2021

Cited by 1 | Viewed by 1346

Abstract

Mucosal Human Papillomaviruses (HPVs) play a role in the development of a subset of head and neck cancers. Cutaneous HPVs are abundantly present in the oral cavity. The determinants of these infections have not been extensively investigated. We assessed the correlates of oral infection by alpha and beta and/or gamma HPVs in HIV-infected and uninfected men who have sex with men (MSM). Oral rinse-and-gargles were collected with a mouthwash. Alpha and beta/gamma HPVs were detected using the Linear Array HPV genotyping test and a multiplex PCR combined with Luminex technology, respectively. Multiple logistic regression was performed to identify independent predictors of oral HPV infection. Overall, 193 HIV-uninfected and 117 HIV-infected MSM were enrolled. Among HIV-infected MSM, the only determinant of alpha HPV infection was the number of lifetime oral sex partners (AOR: 8.26, 95% CI: 2.26–30.16). The strongest determinant of beta/gamma HPV infection was represented by practicing condomless receptive oral sex (AOR: 10.76, 95% CI: 1.56–74.17). Age was independently associated with alpha HPV infection in HIV-uninfected MSM. Beta/gamma HPV infection was not associated with sexual behavior in these subjects. In conclusion, predictors of oral infection differ between HIV-infected and uninfected MSM, as well as between alpha and beta/gamma HPVs. Full article

(This article belongs to the Special Issue Oncogenic Human Papillomaviruses)

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9 pages, 784 KiB

Open AccessArticle

HPV Infection in Middle Ear Squamous Cell Carcinoma: Prevalence, Genotyping and Prognostic Impact

by Giovanni Cristalli, Aldo Venuti, Fabiola Giudici, Francesca Paolini, Fabio Ferreli, Giuseppe Mercante, Giuseppe Spriano and Francesca Boscolo Nata

J. Clin. Med. 2021, 10(4), 738; https://doi.org/10.3390/jcm10040738 - 12 Feb 2021

Cited by 3 | Viewed by 2242

Abstract

Middle ear squamous cell carcinoma (MESCC) is rare. Human Papilloma Virus (HPV) infection has been found in a significant number of cases of MESCC. Despite the emerging role of HPV in oncogenesis, its role in the pathogenesis and prognosis of MESCC is not known. This study aims to identify the prognostic impact of alpha and beta HPV in MESCC and its correlation with p16 protein. We retrospectively investigated 33 patients with MESCC surgically treated between 2004 and 2016. HPV DNA was ascertained by polymerase chain reaction (PCR) and P16INK4a detection was performed. Disease-specific survival (DSS) and cumulative incidence of recurrence were calculated in relation to HPV presence and genotype. p16 sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) in predicting HPV infection were calculated. HPV was detected in 66.7% of patients (36.4% alpha HPV, 63.6% beta HPV). Five-year DSS was 55.0% and was not statistically related to HPV presence (p = 0.55) or genotype (p = 0.87). Five-year cumulative incidence of recurrence was 46 %, and was not statistically related to HPV presence (p = 0.22) or genotype (p = 0.44). p16 sensitivity, specificity, PPV, and NPV in predicting HPV infection were 27.3%, 36.4%, 46.2%, and 20.0%, respectively. In our experience, beta HPV was more frequent than alpha HPV in MESCC. Neither HPV presence nor HPV genotypes relate to DSS or cumulative incidence of recurrence. p16 expression was not predictive for HPV infection in MESCC. The role of HPV infection in oncogenesis, maintenance, and prognosis of MESCC seems to be different from that in oropharynx and skin cancer. Full article

(This article belongs to the Special Issue Oncogenic Human Papillomaviruses)

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Review

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30 pages, 13009 KiB

Open AccessReview

Natural Bioactives: Back to the Future in the Fight against Human Papillomavirus? A Narrative Review

by Silvia Massa, Riccardo Pagliarello, Francesca Paolini and Aldo Venuti

J. Clin. Med. 2022, 11(5), 1465; https://doi.org/10.3390/jcm11051465 - 07 Mar 2022

Cited by 3 | Viewed by 3978

Abstract

Human papillomavirus (HPV) still represents an important threat to health worldwide. Better therapy in terms of further improvement of outcomes and attenuation of related side-effects is desirable. The pharmaceutical industry has always targeted natural substances—phytochemicals in particular—to identify lead compounds to be clinically validated and industrially produced as antiviral and anticancer drugs. In the field of HPV, numerous naturally occurring bioactives and dietary phytochemicals have been investigated as potentially valuable in vitro and in vivo. Interference with several pathways and improvement of the efficacy of chemotherapeutic agents have been demonstrated. Notably, some clinical trials have been conducted. Despite being endowed with general safety, these natural substances are in urgent need of further assessment to foresee their clinical exploitation. This review summarizes the basic research efforts conducted so far in the study of anti-HPV properties of bio-actives with insights into their mechanisms of action and highlights the variety of their natural origin in order to provide comprehensive mapping throughout the different sources. The clinical studies available are reported, as well, to highlight the need of uniformity and consistency of studies in the future to select those natural compounds that may be suited to clinical application. Full article

(This article belongs to the Special Issue Oncogenic Human Papillomaviruses)

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12 pages, 3149 KiB

Open AccessReview

Cervical Human Papillomavirus Infection (HPV) and High Oncogenic Risk Genotypes among Women Living with HIV in Asia: A Meta-Analysis

by Florian Verrier, Sophie Le Coeur and Tristan Delory

J. Clin. Med. 2021, 10(9), 1911; https://doi.org/10.3390/jcm10091911 - 28 Apr 2021

Cited by 7 | Viewed by 2124

Abstract

Women living with HIV (WLHIV) are prone to harbor several high-risk human papillomavirus (HR-HPV) genotypes and to develop cervical cancerous lesions. Data on HPV prevalence in these women are needed to inform immunization programs, especially in Asia where few data are available. We conducted a systematic review and meta-analysis to estimate the prevalence of HPV and HR-HPV cervical infection in WLHIV in Asia and identify possible sources of heterogeneity for HR-HPV carriage. Pooled prevalence and its 95% confidence interval (95CI) were estimated using the inverse-variance weighting method. Linear regression weighted on study size was used to identify sources of heterogeneity. Among 7834 WLHIV (40 studies), the prevalence of HPV infection was 42.6% (95CI, 38.2% to 47.1%), and 34.6% (95CI, 30.3% to 39.1%) harbored HR-HPV genotypes, with significant heterogeneity across countries. In India, Thailand, and China, HPV-16 was the most frequent genotype (10.3%), followed by HPV-52 (5.4%), HPV-58 (5.0%), HPV-18 (4.1%), and HPV-33 (3.3%). In these women, most of whom were receiving antiretroviral therapy, we did not identify determinants of heterogeneity for HR-HPV infection. Our results underline the need for immunization programs based on nonavalent or new generation vaccines to prevent cervical cancer in WLHIV in Asia. Full article

(This article belongs to the Special Issue Oncogenic Human Papillomaviruses)

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24 pages, 625 KiB

Open AccessReview

Circulating HPV DNA in the Management of Oropharyngeal and Cervical Cancers: Current Knowledge and Future Perspectives

by Eriseld Krasniqi, Maddalena Barba, Aldo Venuti, Laura Pizzuti, Federico Cappuzzo, Lorenza Landi, Silvia Carpano, Paolo Marchetti, Alice Villa, Enrico Vizza, Greta Giuliano, Marco Mazzotta, Daniele Marinelli, Sandra Gnignera, Cristina Vincenzoni, Vincenzo Stranges, Domenico Sergi, Antonio Giordano, Federica Tomao, Marcello Maugeri-Saccà, Giuseppe Sanguineti, Francesca Sofia Di Lisa, Silverio Tomao, Gennaro Ciliberto and Patrizia Vici Show full author list Hide full author list

J. Clin. Med. 2021, 10(7), 1525; https://doi.org/10.3390/jcm10071525 - 06 Apr 2021

Cited by 18 | Viewed by 3640

Abstract

Human papillomaviruses (HPVs) are associated with invasive malignancies, including almost 100% of cervical cancers (CECs), and 35–70% of oropharyngeal cancers (OPCs). HPV infection leads to clinical implications in related tumors by determining better prognosis and predicting treatment response, especially in OPC. Currently, specific and minimally invasive tests allow for detecting HPV-related cancer at an early phase, informing more appropriately therapeutical decisions, and allowing for timely disease monitoring. A blood-based biomarker detectable in liquid biopsy represents an ideal candidate, and the use of circulating HPV DNA (ct-DNA) itself could offer the highest specificity for such a scope. Circulating HPV DNA is detectable in the greatest part of patients affected by HPV-related cancers, and studies have demonstrated its potential usefulness for CEC and OPC clinical management. Unfortunately, when using conventional polymerase chain reaction (PCR), the detection rate of serum HPV DNA is low. Innovative techniques such as droplet-based digital PCR and next generation sequencing are becoming increasingly available for the purpose of boosting HPV ct-DNA detection rate. We herein review and critically discuss the most recent and representative literature, concerning the role of HPV ctDNA in OPC and CEC in the light of new technologies that could improve the potential of this biomarker in fulfilling many of the unmet needs in the clinical management of OPC and CEC patients. Full article

(This article belongs to the Special Issue Oncogenic Human Papillomaviruses)

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19 pages, 4324 KiB

Open AccessReview

RG1-VLP and Other L2-Based, Broad-Spectrum HPV Vaccine Candidates

by Bettina Huber, Joshua Weiyuan Wang, Richard B. S. Roden and Reinhard Kirnbauer

J. Clin. Med. 2021, 10(5), 1044; https://doi.org/10.3390/jcm10051044 - 03 Mar 2021

Cited by 27 | Viewed by 3923

Abstract

Licensed human papillomavirus (HPV) vaccines contain virus-like particles (VLPs) self-assembled from L1 major-capsid proteins that are remarkably effective prophylactic immunogens. However, the induced type-restricted immune response limits coverage to the included vaccine types, and costly multiplex formulations, restrictive storage and distribution conditions drive the need for next generation HPV vaccines. Vaccine candidates based upon the minor structural protein L2 are particularly promising because conserved N-terminal epitopes induce broadly cross-type neutralizing and protective antibodies. Several strategies to increase the immunological potency of such epitopes are being investigated, including concatemeric multimers, fusion to toll-like receptors ligands or T cell epitopes, as well as immunodominant presentation by different nanoparticle or VLP structures. Several promising L2-based vaccine candidates have reached or will soon enter first-in-man clinical studies. RG1-VLP present the HPV16L2 amino-acid 17–36 conserved neutralization epitope “RG1” repetitively and closely spaced on an immunodominant surface loop of HPV16 L1-VLP and small animal immunizations provide cross-protection against challenge with all medically-significant high-risk and several low-risk HPV types. With a successful current good manufacturing practice (cGMP) campaign and this promising breadth of activity, even encompassing cross-neutralization of several cutaneous HPV types, RG1-VLP are ready for a first-in-human clinical study. This review aims to provide a general overview of these candidates with a special focus on the RG1-VLP vaccine and its road to the clinic. Full article

(This article belongs to the Special Issue Oncogenic Human Papillomaviruses)

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