Discovery Of Human Papillomavirus Research Articles

Looking Back, Moving Forward: Challenges and Opportunities for Global Cervical Cancer Prevention and Control.

Despite the introduction of Pap testing for screening to prevent cervical cancer in the mid-20th century, cervical cancer remains a common cause of cancer-related mortality and morbidity globally. This is primarily due to differences in access to screening and care between low-income and high-income resource settings, resulting in cervical cancer being one of the cancers with the greatest health disparity. The discovery of human papillomavirus (HPV) as the near-obligate viral cause of cervical cancer can revolutionize how it can be prevented: HPV vaccination against infection for prophylaxis and HPV testing-based screening for the detection and treatment of cervical pre-cancers for interception. As a result of this progress, the World Health Organization has championed the elimination of cervical cancer as a global health problem. However, unless research, investments, and actions are taken to ensure equitable global access to these highly effective preventive interventions, there is a real threat to exacerbating the current health inequities in cervical cancer. In this review, the progress to date and the challenges and opportunities for fulfilling the potential of HPV-targeted prevention for global cervical cancer control are discussed.

Discovery of Human Papilloma Virus and patient-specific neoantigens targeted by CD8+ T cells in HNSCC

Abstract Head and neck squamous cell carcinoma (HNSCC) is amongst the rapidly growing form of cancer associated with high mutation burden and Human Papilloma virus (HPV) infection presenting approximately 800,000 new cases and 400,000 deaths annually. HPV-positive (HPV) HNSCC has been strongly associated with better prognosis than HPV-negative HNSCC due to the immune activation in the tumor microenvironment including cytotoxic CD8+ T cells. One of the key missing links is the relative contribution of HPV-reactive and neoantigen-reactive CD8+ T cells in anti-tumor response. To address this, we utilized epitope libraries presented in Signaling and Antigen-presenting Bifunctional Receptors (SABRs), which were previously described by our lab. As a proof-of-concept, we generated SABR libraries presenting 8392 epitopes derived from HPV or from personalized neoantigens from five HNSCC patients. In parallel, we used single cell RNA sequencing to identify 25 clonally expanded TCRs from tumor-infiltrating lymphocytes of the patients. Using SABR screens, we have identified several putative HPV-derived and neoantigen-derived epitopes targeted by CD8+ T cells in HNSCC patients. We have established a robust pipeline for identification of patient-specific epitope specificities from tumor-infiltrating CD8+ T cells. The goal is to determine whether and how effective anti-HPV or anti-neoantigen T cell responses may contribute to therapeutic efficacy using human samples from clinical trials and murine HNSCC models. Our study will aid in the discovery of novel tumor-associated antigens in HPV+ HNSCC patients, which can be successfully employed for precise adoptive T cell transfer therapies.

Therapeutic strategies:Surgery for human papillomavirus-associated oropharyngeal carcinoma.

Treatment of oropharyngeal cancer (OPC) has undergone considerable evolution since the discovery of human papillomavirus (HPV)-associated OPC. It is widely understood that HPV OPC affects a younger population and standard treatment offers improved oncologic outcomes compared with non-HPV OPC but can cause significant toxicities and long-term side effects. Surgery for treatment de-escalation is an active area of research. The purpose of this review is to explore surgery as it relates to the treatment of HPV OPC with a focus on the evolution of treatment, rationale for surgery, surgical techniques, outcomes, and the role of surgery in de-escalation of treatment.

Biosensors Based Medical Devices For Disease Monitoring Therapy

A Biosensor is a bio-analytical device which is used to collect physical, chemical or biological information and then convert that information into an electrical signal. Nowadays Biosensors are distributed over a considerable extent in biomedical diagnosis and a broad variety of other fields like monitoring of treatment and progression of disease, environment and agriculture monitoring, food safety, discovery of drug, biomedical & forensics research. The first biosensor was designed over a century ago in 1906, but it was clearly defined & established later in 1956. A broad range of techniques can be used for biosensor growth and their combination with high affinity biomolecules enable a variety of analysts to be sensitive & selective. Biosensors and their importance in medical science which includes human’s early stage of detection of interleukin-10 causing heart diseases, fast discovery of human papilloma virus, etc. are various important aspects. Fluorescent biosensors also play a very important role in discovery of drug and in cancer. Biosensor applications are ubiquitous in the plant biology segment to discover out the missing links which is required in metabolic processes. Other applications are implicated in defense, clinical sector, marine applications and also biosensor illustrates the span of bimolecular sensing strategies with the growth of nanotechnology approaches that are now available.

Cervical Cancer Screening—Past, Present, and Future

Cervical cancer screening has undergone a transformation in recent decades. Historically, programs were based on cervical cytology (i.e., "Pap smear"), which had to be repeated often because of its limited sensitivity and reproducibility. In more recent years, the discovery of human papillomavirus (HPV) as the necessary cause of virtually all cervical cancers has led to the introduction of HPV testing into clinical practice, first as a triage test for minor cytologic abnormalities, then in conjunction with cervical cytology (cotesting), and most recently, as a standalone screening test. Multiple randomized trials have shown that HPV-based screening has higher sensitivity compared with cytology, providing great reassurance against cervical precancer and cancer for women testing HPV-negative for many years. Analyses have also been conducted in support of the recent U.S. Preventive Services Task Force guidelines that show that primary HPV screening achieves the greatest balance of benefits and harms compared with other strategies. An added benefit of primary HPV testing is the ability to conduct it from self-collected samples, which is critical for extending coverage among hard-to-reach individuals and could provide a safe and effective alternative to in-person screening visits during the COVID-19 pandemic.See related article by Liang et al., p. 474.

De-escalation in HPV-associated oropharyngeal cancer: lessons learned from the past? A critical viewpoint and proposal for future research.

Among head and neck squamous cell carcinomas (HNSCCs), oropharyngeal cancer (OPC) was historically thought to be a homogenous entity, mainly caused by excessive alcohol and tobacco consumption. However, the discovery of human papillomavirus (HPV) infection as an independent risk factor for the development of OPC has led to changes in diagnostics and treatment of this cancer. HPV-positive OPC is associated with improved survival and reduced recurrence rates compared to similar stage HPV-negative OPC and HNSCC in general. These favorable outcomes have led the medical and scientific communities to consider de-escalation treatment options in this specific population to spare patients from unnecessary toxicity, without compromising survival. This comment aimed to critically evaluate de-intensification treatment strategies in HPV-related OPC and to propose future treatment approaches as well as trial design. A review of the literature was performed. Among nine published non-surgical de-intensification trials, only three studies had a comparison head-to-head with the standard of care, with two trials demonstrating clear inferiority of de-escalating treatment option (cetuximab-based radiotherapy). Additionally, there has been significant heterogeneity among induction chemotherapy (IC) protocols in de-escalating studies. Also, the toxicity among these studies varies in terms of the manner of reporting (physician vs patient-reported adverse events). Data obtained with de-intensified strategies should only serve to help select an appropriate experimental arm for a randomized controlled trial phase III comparison against cisplatin and 70Gy of radiotherapy. Without a proper randomized trial, there remains the possibility of compromising survival, which raises ethical questions about conducting any de-escalation trial.

Paediatric Virology as a new educational initiative: An interview with Nobelist Professor of Virology Harald zur Hausen.

Born in Gelsenkirchen-Buer in Germany on March 11th, 1936, Professor Harald zur Hausen, Emeritus Professor of Virology at the University of Freiburg and 2008 Nobel Prize Laureate in Physiology or Medicine for his discovery of human papillomavirus (HPV), which causes cervical cancer, believes that good knowledge of virological methods and diagnostic possibilities are an asset for all young paediatricians. Professor zur Hausen considers that the creation of an educational platform on Paediatric Virology is definitely very beneficial for young paediatricians, as this will greatly enhance their knowledge in the field of Virology. He very actively advocates the vaccination of boys for the eradication of HPV infection and emphasises that male HPV vaccination should be included into the current vaccination programmes. He would have certainly considered Dr George N. Papanicolaou (Kyme, Island of Euboea, Greece, 1883 - Miami, Florida, USA, 1962) as an excellent candidate for the Nobel Prize, stating that the contribution of Dr Papanicolaou did not find sufficient recognition in the past. In the context of the 3rd Workshop on Paediatric Virology, which will be held in Athens, Greece, on October 7th, 2017, Professor zur Hausen will give his plenary lecture on ‘Paediatric Virology and Oncology: Virus persistence and the important first years of life’.

Carcinogenic human papillomavirus infection.

Infections with human papillomavirus (HPV) are common and transmitted by direct contact. Although the great majority of infections resolve within 2 years, 13 phylogenetically related, sexually transmitted HPV genotypes, notably HPV16, cause - if not controlled immunologically or by screening - virtually all cervical cancers worldwide, a large fraction of other anogenital cancers and an increasing proportion of oropharyngeal cancers. The carcinogenicity of these HPV types results primarily from the activity of the oncoproteins E6 and E7, which impair growth regulatory pathways. Persistent high-risk HPVs can transition from a productive (virion-producing) to an abortive or transforming infection, after which cancer can result after typically slow accumulation of host genetic mutations. However, which precancerous lesions progress and which do not is unclear; the majority of screening-detected precancers are treated, leading to overtreatment. The discovery of HPV as a carcinogen led to the development of effective preventive vaccines and sensitive HPV DNA and RNA tests. Together, vaccination programmes (the ultimate long-term preventive strategy) and screening using HPV tests could dramatically alter the landscape of HPV-related cancers. HPV testing will probably replace cytology-based cervical screening owing to greater reassurance when the test is negative. However, the effective implementation of HPV vaccination and screening globally remains a challenge.

HPV vaccination: for women of all ages?

The discovery of human papillomavirus (HPV) DNA in cervical cancer by Harald zur Hausen sparked 30 years of research that established that persistent cervical infection by certain HPV genotypes causes cervical cancer. This research has led to revolutionary technical advances for the prevention of cervical cancer: prophylactic HPV vaccination and sensitive molecular HPV testing for screening. These promising technologies can be used to complement or enhance established cervical cancer prevention programmes, and to provide robust solutions in low-resource settings without screening programmes.

Cervical cancer screening at crossroads.

Cervical screening has been one of the most successful public health prevention programmes. For 50 years, cytology formed the basis for screening, and detected cervical intraepithelial lesions (CIN) were treated surgically to prevent progression to cancer. In a high-risk country as Denmark, screening decreased the incidence of cervical cancer from 34 to 11 per 100,000, age-standardized rate (World Standard Population). Screening is, however, also expensive; Denmark (population: 5.6 million) undertakes close to half a million tests per year, and has 6-8 CIN-treated women for each prevented cancer case. The discovery of human papillomavirus (HPV) as the cause of cervical cancer dramatically changed perspectives for disease control. Screening with HPV testing was launched around 1990, and preventive HPV vaccination was licensed in 2006. Long-term randomized controlled trials (RCT) demonstrated that HPV testing provides better protection against cervical cancer than cytology, but it requires extra repeated testing. HPV vaccination RCTs, furthermore, have proved that HPV vaccination protects against vaccine-type high-grade CIN in women vaccinated prior to sexual activity, but less so in women vaccinated later. The challenge now is therefore to find an algorithm for screening of a heterogeneous population including non-vaccinated women; women vaccinated prior to start of sexual activity; and women vaccinated later.

Human papillomavirus and non-small cell lung cancer.

Lung cancer is the most common cause of cancer-related deaths in the world, causing more than one million deaths worldwide each year. Human papillomavirus (HPV) are small non-enveloped DNA viruses that infect squamous epithelial cells. Relevant studies have reported lung cancer-related HPV infection rates that fluctuate between 10% and 80%, depending on the various research methods and geographical factors. Various scholars gathered statistics from global research reports and found that 22.4% of the patients with lung cancer presented with an HPV infection, which suggested that HPV infection may relate to the tumorigenesis of non-small cell lung cancer. This article will review the history and discovery of HPV, the correlation between HPV and lung cancer development, and carcinogenesis caused by HPV regulatory genes, such as p53, p21, p16INK4a, and genes related to hypermethylation and genome instability in lung cancer patients with HPV infection. In addition, because studies have highlighted the difference in clinical prognosis for HPV-positive and HPV-negative patients, articles demonstrating the correlation between HPV infection and prognosis for lung cancer patients will be reviewed.

Laboratory Management of Cervical Intraepithelial Neoplasia

Since the discovery of human papillomavirus (HPV) type 16 in early 80s, the link between HPV and cervical cancer has been established with certainty, a function of the discovery and cloning of a range of HPV types associated with both cancer precursors (cervical intraepithelial neoplasia or CIN) and carcinomas and extensive epidemiologic, clinical, pathologic, and experimental data. These accumulated results have culminated in new paradigms of cancer prevention through screening and triage. Despite this, the management of women with CIN is still suboptimal and the overtreatment of these conditions still occurs, largely due to the lack of clarity regarding which precancerous lesions are most likely to progress in grade. Recently, a discrete population of cuboidal cells was discovered at the cervical squamocolumnar junction, the anatomic site where the large majority of HPV-related (pre)neoplastic lesions develop. These cells seem to be embryonic in nature and participate both in benign metaplasias and the initial phase of precancer development. This review summarizes the historical evolution of precursor management, assesses the potential role of this and other discoveries in segregating lower from higher-risk precursors, and examines their potential impact on the management of women with real or potential cervical cancer precursors.

The role of human papillomavirus in oral squamous cell carcinoma: myth and reality

As the traditional risk factors for oral squamous cell carcinoma, especially tobacco, decline, new potential causative agents become the focus of research. Since the discovery of human papillomavirus (HPV) and its importance in carcinogenesis in cervical cancer, a lot of research has been undertaken to define its role in different types of cancer. In the present study, we evaluate the role of high-risk HPV types in initiation and progression of oral squamous cell carcinoma (OSCC) using a systematic review of the current literature. A literature research with the search term "HPV oral squamous cell carcinoma" was performed via PubMed. Results were screened systematically for relevance and classified into the following categories: molecular biology, genetics, clinical aspects, and prevalence. Articles were then further analyzed to assess quality. The literature research led to 527 results, with an overall HPV prevalence of 30.1 % in OSCCs. The most frequently identified subtypes were HPV-16 and HPV-18 (25.4 and 18.1 %, respectively). Prognostic relevance of HPV was discussed controversially. HPV detection via polymerase chain reaction is the most established method today. Molecular changes according to carcinogenic pathways described for cervix carcinoma were not routinely found in OSCC. In general, no definite role of high-risk HPV is currently deducible from the literature. High-risk subtypes 16 and 18 are present in the genome in approximately one third of OSCC. Its role as a causative agent is less clear than the role in oropharyngeal tumors. The infection might not be the cause of carcinogenesis in a significant number of patients but may become proportionally more important with the decrease of the classical risk factors of tobacco and alcohol.

Non transmissible diseases are often transmissible

In the work, and in the comments on the work of Nicoll and Sprenger [1], Keil [2] recalled that, in addition to diseases considered as transmissible diseases (which are still the cause of 1/3 of direct deaths), it is imperative to focus attention on non transmissible diseases [3]. What I find amazing, including in the authors’ response [4], is to continue to call non transmissible diseases or non communicable diseases, the chronic diseases, (including cancer and cirrhosis), which are undoubtedly caused by transmissible agents. It is surprising that despite the recent Nobel Prize to B. J. Marshall and J.R. Warren for the discovery of Helicobacter pylori, which is undoubtedly the major agent of gastric cancer, Von Hausen for his discovery of Human Papillomavirus which is the agent of cervical uterus cancer, anal cancers and part of throat cancers, whereas liver cancers are almost always caused by hepatitis B or hepatitis C viruses, and that Kaposi’s sarcoma, that is so common in Africa, is caused by HHV8 [3]. As much of 25% of lymphoma are associated with Epstein Barr virus (EBV), as well as the Burkitt’s B-cell lymphoma and nasopharyngeal carcinoma. Burkitt’s lymphoma (BL) is a malignant form of tumor associated with EBV that is endemic to central parts of Africa and New Guinea. Moreover, most of liver cirrhosis are associated to hepatitis viruses. Indeed it is hardly understandable that these are called ‘‘non transmissible’’ or ‘‘non communicable’’. Instead, based on what Ulrich Keil said, it appears likely that the best prevention of these cancers (which represent between 15% and 40% of total cancer cases by region) [2] will be obtained the vaccination, provided that the benefits and costs of such vaccine should be studied in a reasonable manner and presented in an acceptable manner to the population. Anyway, it’s time, including the best vehicles of the information like The Lancet [5], Science [6], WHO ( http://www.who.int/topics/chronic_diseases/en/ and the ECDC (http://repositorio.insa.pt/bitstream/10400.18/281/1/ National%20Public%20Health%20Institutes.European%20 perspective.pdf) should abandon the term of non-transmissible diseases for diseases that are related to an infection transmitted through sexual contact, saliva, or by injection.

HPV and Therapeutic Vaccines: Where are We in 2010?

The discovery of human papillomavirus (HPV) as a necessary etiological factor for cervical cancer has spurred the development of preventive and therapeutic HPV vaccines for the control of HPV-associated malignancies including cervical, vulvar, vaginal, and a subset of head and neck cancers. The commercial preventive HPV vaccines, Gardasil and Cervarix, use HPV virus-like particles to generate neutralizing antibodies against HPV major capsid protein L1. However, they do not exert therapeutic effects on existing lesions and are unlikely to have an immediate impact on the prevalence of cervical cancer due to their cost and limited availability in developing countries, which account for more than 80% of cervical cancers. Thus, there is an urgent need for therapeutic HPV vaccines. Therapeutic HPV vaccines can eliminate preexisting lesions and infections by generating cellular immunity against HPV-infected cells. HPV E6 and E7 oncoproteins represent ideal targets for therapeutic intervention because of their constitutive expression in HPV-associated tumors and their crucial role in the induction and maintenance of HPV-associated disease. This review discusses the current progress of various therapeutic HPV vaccine approaches, including live vector-based, peptide/protein-based, nucleic acid-based and cell-based vaccines targeting E6 and/or E7 antigens, and their future prospects for the control of HPV-associated malignancies.

Interaction Between Interferon Regulatory Factor-1 and Human Papillomavirus E7 Oncogene in Cervical Cancer: An Ontology Study

Cervical cancer is an important female malignancy. The discovery of human papillomavirus (HPV) as an etiologic agent of cervical cancer has prompted increased interest in the biology and oncogenicity of this virus. The E7 protein is found predominantly in the nucleus and, to a lesser extent, in the cytoplasm in cervical cancer cell lines. HPV E7 has been shown to be functionally associated with the tumor suppressor interferon regulatory factor (IRF)-1 in cervical carcinogenesis. In this study, new gene ontology technology was used to predict changes in the molecular function and biologic processes caused by the interaction between IRF-1 and HPV E7. The molecular function and biologic processes of IRF-1 and the combined IRF-1 and HPV E7 (IRF-1-E7) were derived using the GoFigure server. The combined IRF-1-E7 demonstrated more functions and biologic processes compared with IRF-1 alone. IRF-1-E7 was shown to be responsible for the positive regulation of many interleukins and to be involved in the differentiation of T-helper cells.

Human papillomavirus vaccines

Cervical and other cancers linked to the human papillomavirus (HPV) are a cause of significant morbidity and mortality. Since the discovery of HPV as a cause of these cancers, there has been much research and development in the field of HPV vaccination. Two current prophylactic vaccines have proved highly effective in preventing disease because of the vaccine types. Recent advances in prophylactic and therapeutic vaccines are discussed.

Molecular basis of cervical carcinogenesis by high-risk human papillomaviruses

Over the last two decades since discovery of human papillomavirus (HPV) type 16 and 18 DNAs in cervical cancers by Dr. Harald zur Hausen, HPVs have been well characterized as causative agents for cervical cancer. Viral DNA from a specific group of HPVs can be detected in at least 90% of all cervical cancers and two viral genes, E6 and E7, are invariably expressed in HPV-positive cervical cancer cells. Their gene products are known to inactivate the major tumor suppressors, p53 and pRB, respectively. In addition, one function of E6 is to activate telomerase, and E6 and E7 cooperate to effectively immortalize human primary epithelial cells. Though expression of E6 and E7 is itself not sufficient for cancer development, it seems to be either directly or indirectly involved in every stage of multi-step carcinogenesis. Indeed, it has been shown that only one or two genetic alterations in addition to expression of E6 and E7 are experimentally sufficient to confer tumorigenicity to normal human cervical keratinocytes. Epidemiological and biological studies suggest the potential efficacy of prophylactic vaccines to prevent genital HPV infection as an anti-cancer strategy. However, given the widespread nature of HPV infection and unresolved issues about the duration and type specificity of the currently available HPV vaccines, it is crucial that molecular details of the natural history of HPV infection as well as the biological activities of the viral oncoproteins be elucidated in order to provide the basis for development of new therapeutic strategies against HPV-associated malignancies. This review highlights the novel functions of E6 and E7 as well as the molecular mechanisms of HPV-induced carcinogenesis.

2008 Nobel Prize for Medicine or Physiology for discovery of HPV and HIV viruses – short history of discovery of HIV

Summary In 2008 the Nobel Prize for Medicine or Physiology was divided and half of it awarded discovery of the human papilloma virus (HPV) and its correlation with women's cervical cancer, and the other half – discovery of the human immunodeficiency virus (HIV). The latter part raised many comments and controversies. As 25 years have passed since the HIV virus was identified, the short history of this discovery was recalled, as it is quite forgotten now.

Human papillomaviruses, cervical cancer and the Developing World

Carcinoma of the uterine cervix is the commonest cancer of women in the majority of developing countries; in developed countries it is much less common, as well as being less frequent than some other cancers, such as those of breast, lung and colon. The discovery of human papillomavirus (HPV) as an aetiological agent of cervical cancer (and of other anogenital malignancies) has prompted a great deal of interest in the biology and oncogenicity of this virus, including large-scale epidemiological surveys comparing the prevalence of HPV and other possible causative agents between areas of high and low incidence of cervical carcinoma. These studies have thrown up tantalizing clues concerning the virus' pathogenesis and disease associations. Sexual practices, parity, diet, smoking, other diseases (including sexually transmissible diseases) and immunogenetic characteristics may all play a contributory role in the development of cervical carcinoma. These factors may be independent of each other and of association with HPV infection. Immunization to prevent papillomavirus infection and thus cervical cancer is an attractive prospect. Although the potential in using such an approach has been demonstrated in several animal models, there are several major theoretical problems to solve before HPV vaccination becomes a practicality. Intervention to prevent exposure to other aetiological factors and to improve screening may be a more practicable strategy for reducing the burden of cervical cancer.