Genital Warts (HPV Infection) Causes, Symptoms, Treatment

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Condylomata acuminata

Condylomata acuminata are caused by human papillomaviruses (HPV). They are usually present as genital warts, but other locations (oral) are known to be involved. HIV-infected patients have a higher risk of acquiring genital warts. The typical pathogens, human papillomavirus type 6 or type 11, are not normally considered to be cancerogenic. Although, in both male and female HIV-infected patients, epithelial atypia is seen more often than in uninfected persons. Besides sexual transmission, infection with papillomavirus may be possible via smear infection and perhaps through contaminated objects. But the primary risk factor remains the number of sexual partners (Karlsson 1995).

Laryngeal papilloma

The juvenile form is believed to be acquired during birth from maternal vaginal warts. The condition does not manifest, however, until months or years later when significant papillomata develop. In general, those who present early usually present with airway obstruction, while older children usually present with progressive hoarseness. Treatment is extremely difficult and frequent recurrence is a rule rather than exception. At laryngoscopy, there is usually extensive involvement of the whole larynx simultaneous tracheal and pharyngeal involvement by the papillomata is not uncommon. Repeated CO2 laser therapy offers the best control of the disease. In severe cases, antiviral therapy including interferon therapy may be tried. Although the effectiveness of treatment is unpredictable, spontaneous regression of the papilloma may occur at any age. The adult form typically presents with progressive hoarseness and laryngoscopy, and reveals either a solitary papilloma or multiple but discrete...

Lucky Day For Two Neuropathologists And More Luck On A Sabbatical

And we could not believe our luck and kidded about the influence of the Bacardi. After Dr. Chou developed the first photographic plates that also revealed scattered virions and filamentous forms, we hugged in the dark room what an exciting day in our lives it was. Whereas the tissue in general showed moderate autolysis, the virions were so well preserved that their images compared favorably with those in the literature. The virions belonged to an identifiable group, with oncogenic potential, perhaps explaining the bizarre shapes of as-trocytes, and this virus had penetrated deep into the brain, unlike papilloma viruses. Yet no human polyoma virus was known at that time. When we showed the plates to Dr. Angevine, his dry comment was This is the way discoveries are being made.''

The Selling Of The Apples Acceptance Collaborations And Invitations

Well, our ''apples'' sold fast and widely. Science published our first paper (Zu Rhein and Chou, 1965). Dr. Zimmerman had agreed that we should not wait for the publication of the ARNMD volume, which indeed became delayed for 4 years. A neighbor in the Bronx was Dr. Ludwik Gross, Director of the Cancer Research Unit of the VA Medical Center. A pioneer in virus research, he had stood at the cradle of the polyoma virus. Some of his work had also been met with disbelief early on. He was a virologist well versed in viral morphology. When he reviewed our PML electron micrographs, he shared our interpretation with enthusiasm. He invited me subsequently to join him in a research seminar on ''Viruses in Disease.'' We stayed in close contact for the later editions of the Oncogenic Viruses. Dr. Richard Shope (Rockefeller University), discoverer of the rabbit papilloma virus, also became an immediate supporter during a laboratory visit. ''You are in business'' he told me with confidence and true...

Regulation of p53 function

It was demonstrated some years ago that human papilloma viruses (HPV), especially HPV 16, 18 and also some other types, are associated with high-grade cervical intraepithelial neoplasia (CIN) and invasive cervical squamous carcinomas. The integration of these viruses in the genome results in increased expression of the proteins known as E6 and E7, and these proteins have the ability to transform cells into the neoplastic state. Immunohistochemical studies have shown co-localisation of p53 phosphoprotein and E6, suggesting an association between them (Liang et al., 1993). It would appear that the E6 protein binds the p53 phosphoprotein (Werness et al, 1990). This requires another cellular factor called the E6-associated protein (E6-AP). This event leads to a rapid degradation of p53 protein, mediated by ubiquitin-dependent proteolysis (Huibregtse etal., 1993). The introduction of a single HPV16-E6 gene causes the immortalisation of cells and sharply reduces p53 protein levels (Band et...

Kenneth Lundstrom PhD Contents

Alphavirus vectors can infect a broad range of mammalian cells both in cell cultures and in vivo. The presence of the RNA replicon generates extreme RNA levels in infected cells, which is the basis for the very high levels of heterologous gene expression. Application of replication-deficient vectors leads to short-term expression, which makes these vectors highly attractive for cancer gene therapy. Alphaviruses can be used as vaccine vectors for both prophylactic and therapeutic applications. In this context, the P185 tumor antigen and human papilloma virus gene E7, when administered in mice, resulted in protection against tumor challenge and tumor regression in animals with pre-existing tumors. Alphavirus vectors carrying therapeutic or toxic genes used for intratumoral injections have demonstrated efficient tumor regression. For systemic delivery, expression targeting has been obtained by the introduction of targeting sequences in the envelope structure of the virus. Alternatively,...

Alphavirus Used In Cancer Vaccines

Alphavirus vectors have frequently been applied for vaccine production. In this context, recombinant particles as well as naked nucleic acids have been applied. The proof of concept was originally demonstrated for viral surface proteins known for their potential immunogenicity and capability to induce cytotoxic T-cell (CTL) responses and protection against challenges with lethal viruses (20). Moreover, immunization against tumor challenges has resulted in some promising observations (Table 1). For instance, injection of RNA from an SFV vector expressing bacterial -galactosidase into mice provided protection against tumor challenges (21). Administration of recombinant SFV particles expressing the P1A gene resulted in protection against P185 tumor challenges in mice (22). The human papilloma virus (HPV) E6 and E7 oncoproteins have been

VSV Gene Therapy and Vaccines

Designed to protect against respiratory syncytial virus (RSV), human papillomavirus (HPV), and viruses associated with acquired immunodeficiency syndrome (AIDS), amongst others (88-91,93-96). In addition, new generations of attenuated, nonpropagat-ing viruses are being developed where the VSV G protein has been deleted. These non-propagating viruses (AG) lacking G, which is essential for infectivity, are generated via helper-cells that supply the VSV G glycoprotein in trans (29,88,97). Budding viruses incorporate the G protein on their surface and are released. Such viruses can infect cells through the highly tropic G protein and commence replication. However, AG progeny viruses, when released from their primary targets, cannot infect other cells because they lack the G protein gene product. In vaccine studies, such viruses have been shown to retain their protective efficacy compared with their wild-type, replication competent counterparts, yet are considerably attenuated (88,97)....

Retinoblastoma susceptibility gene rb abnormalities in cancer

Consistent with these thoughts is the observation by Wrede et al. (1991) that no abnormalities of rb or p53 are detectable in human papilloma virus (HPV> positive cervical carcinoma cell lines. The rb protein expressed in these cell lines was of the wild-type (Scheffner et al., 1991), but evidence of abnormalities are found in HPV-negative cell lines. Riou et al. (1992) found that early-stage invasive cervical cancers which over-express the myc oncogene in the absence of HPV show a high risk of distant metastases, thus myc gene over-expression may be deemed as an independent prognostic indicator of metastasis.

Regulation of cell cycle progression by retinoblastomasusceptibilitygene product

The sequestration of unphosphorylated rb protein will allow the cells to transit into the S-phase. It is known that functional rb protein forms stable complexes with transforming oncoproteins such as those encoded by the simian virus 40 (SV40) and human papilloma viruses (Templeton et al, 1991). HPV E7 binds to rb protein and such binding is necessary for E7 protein to immortalise and transform cells (Dyson et al., 1989 Munger et al, 1989 Gage et al, 1990). The SV40 T-antigen is known to bind preferentially to the underphosphorylated rb protein (Ludlow et al., 1989). Although these studies suggest a close correlation between phosphorylation and the transition of cells from G, into the S-phase of the cell cycle, phosphorylation might be a progressive event and this may be reflected in the molecular heterogeneity found in rb proteins (Xu et al., 1989). The process of rb phosphorylation may be an incremental process beginning in late G,, several hours before transition into the S-phase

Identification Of A New Virus

On October 7, 1970, a midstream urine sample, collected a day earlier, arrived in the laboratory from a Sudanese patient who had received a renal transplant from his brother on June 24, 1970. A phone call the same day from St. Mary's Hospital informed us that this urine contained many inclusion-bearing cells, and so electron microscopy examination would be well worthwhile. Two days later, Anne Field saw very large numbers of papovavirus particles in the high-speed urine pellet and suggested that they were particles of common wart virus (the only human papovavirus known at the time). It was queried whether the patient had genital warts a report earlier that year (Spencer and Andersen, 1970) had described a high incidence of warts after renal transplantation. Ultrathin sectioning of the cells in a subsequent urine sample collected on October 12 from the same patient showed many virus particles within enlarged cell nuclei. Measurement of the virus particles (45 nm diameter) showed the...

Strategies Using Nonviral Vectors In Cancer Gene Therapy

Electroporation (66,67), resulting in significantly induced cytokine levels or specific antigen expression. Electroporation has also been used to introduce plasmids that encode antisense RNA against E6 and E7 mRNA to human papilloma virus (HPV) expressing cancer cells, which resulted in a significant inhibition of tumor growth (68). Another approach involved gene gun-mediated delivery of heat-shock protein 70 (Hsp70) linked to the HPV16 E7 tumor antigen gene into antigen presenting cells (APCs). It led to an enhanced E7-specific immune response of lymphocytes after exposure to these transfected APCs (69).

Screening and Cancer Control

This chapter focuses on the use of screening for cancer. Cancer is a leading cause of death worldwide, and in 2007 accounted for 7.9 million deaths (around 13 of all deaths), a figure that is predicted to rise to 12 million by 2030 (WHO, 2009). Screening represents a major part of the cancer control effort, particularly in developed countries. The Papanicolaou (Pap) test for the detection of pre-cancerous cervical lesions is the most widely used cancer screening test. It was developed in 1928 and is now available to women across the globe albeit with different technologies and test frequencies. Some cervical cancer screening programs now also incorporate DNA testing for human papillomavirus (HPV), the viral precursor to cervical cancer. Mammography screening was developed in the 1950s for early diagnosis of breast cancer and involves taking a low-energy X-ray of the breast which is then examined for signs of calcification or soft tissue masses. More recently, colorectal cancer (CRC or...

Provision of Cancer Screening Services

Cervical screening is currently offered to women in most developed countries. This is usually by Pap testing, but there has recently been a move to using liquid-based cytology in some countries. The USA and Canada offer cervical screening opportunistically, but organized programs are offered in Australia, the UK, and some other European countries. In a survey of 25 European screening centers (from 18 countries), organized screening was offered by 15 and opportunistic screening by 10 centers (Anttila et al, 2004). The age that cervical screening starts ranges from 18 to 30 years, and screening usually finishes between 60 and 69 years. Recommended screening intervals vary widely across countries (from 1 to 10 years) and in some countries depend on the age of the woman and whether she has had a previous abnormal result. Across Europe, the number of Pap tests a woman has in her life time therefore ranges from 7 to 50 (Anttila et al, 2004).

Optimizing Screening Uptake

In most developed countries, uptake of cervical screening is good. The most recent figures in the UK show that 79 of women aged 25-64 years have been screened within the last 5 years (2008-2009 figures NHSCSP, 2009), and in Australia the equivalent figure for women aged 20-69 years is 86 2006-2007 figures Australian Institute of Health and Welfare (AIHW), 2009b . Across Europe, uptake of cervical screening at the recommended intervals ranges from 30 to 93 and is greater than 75 for six countries Finland, Sweden, UK, Denmark, Iceland, and the Netherlands (Anttila et al, 2004). In the US National Health Interview Survey, 83 of American women aged 18 or older reported having had a Pap test in the preceding 3 years (2000 data Solomon et al, 2007). Similarly in the Canadian National Population Health Survey, 79 of women aged 20-69 said they had had a Pap test within the previous 3 years (data from 1998-1999).

Impact of Abnormal Results

The introduction of HPV testing into cervical cancer screening brings with it the negative psychological consequences that are more often associated with testing for sexually transmitted infections, including feelings of stigma and shame as well as concerns about transmission, and questions about where the virus has come from, with the associated issues of trust and fidelity (McCaffery et al, 2006). In addition, poor understanding of the meaning of an HPV result can lead to heightened anxiety, at least in the short term (Maissi et al, 2004).

Shift of Boundary Between Risk and Disease

For a disease that is as much feared as cancer, this is a powerful motive for the public too. However expansion of screening programs may also increase people's sense of risk or to put it the other way, undermine the illusion of health. With some screening programs identifying precursor risks (e.g. HPV infection) in a much higher proportion of the population than would ever have been likely to develop cancer, then the barriers between health and disease are blurred further. This is striking in the metabolic field where huge proportions of the population are identified with hypertension, insulin resistance, or hyperlipidemia, potentially creating an almost population-wide perception of compromised health status. The growth in personalized genetic testing - which will increasingly offer quantitative risk feedback rather than just testing for the presence or absence of highly penetrant mutations, will also add to the blurring of boundaries between health, disease risk, and disease....

Tumor Induced Changes In Mhc Class I Presentation Of Hostderived Peptides

Additionally, tumors display classical or universal stress responses that are easily identifiable with other disease states, such as viral infection. Indeed, a number of cancers are induced by viral infection by such agents as Epstein Barr Virus and Human Papilloma Viruses. Universal stress induced responses identified in tumor cells include up-regulation of MHC class I, Hsp72, and the NK cell ligands MHC-like MICA and MICB. Interestingly, these common stress induced genes are located within the MHC class I loci of chromosome 6 (Collins, 2004). In addition, many transcriptional regulators and translational regulators are over-expressed by both tumors and virally infected cells, including Stat-1, p68 and eIF4G (Abbas et al., 2000 Bates et al., 2005 Clemens, 2004).

Nora A Janjan John M Skibber Miguel A Rodriguez Bigas Christopher Crane Marc E Delclos Edward H Lin and Jaffer A Ajani

Anal cancer is a rare neoplasm, accounting for less than 2 of all cancers of the digestive tract. Despite its rarity, specific risk factors for anal cancer development have been identified. High rates of human papillomavirus (HPV) infection have been observed in anal cancer, and an increased risk of anal HPV infection has been demonstrated in HIV-seropositive patients. An inverse relationship has been shown between the CD4 count and HPV infection. Immunosuppression from other causes, like organ transplantation, increases the risk of anal cancer by a factor of 100. Smoking increases the risk of anal cancer by a factor of 2 to 5 conversely, a prior diagnosis of anal cancer increases the risk of lung cancer by a factor of 2.5.

Extending the Life Span of Muscle Cells

Since the moderate proliferative capacity of primary human skeletal muscle cells is a limiting factor in studies for which large numbers of myoblasts are required, several groups have tried to immortalize human myoblasts, or at least to extend their life span 123-128 . Transfection of human myoblasts with constructs that carry the gene encoding the SV40 large T antigen resulted in an extended life span of these cells while their capacity to differentiate in a nearly physiological manner was more or less well preserved. Expression of the T antigen has been used to immortalize several cell types of human origin 129 . This immortalization depends on the inactivation of tumor suppressor proteins p53, retinoblastoma gene product (RB), and the RB-related proteins p107 andp130 130 . RB, in turn, seems to bind and inactivate MyoD and myogenin, thus inhibiting dedifferentiation of myotubes 131, 132 . Therefore, in myoblasts the expression of the T antigen has to be switched off in order to...

Biological Functions of Rb and E2F

E2F can also be released from E2F Rb complexes by viral oncogenes such as the SV40 large T antigen or by the human papilloma virus E7 protein. The strains of HPV that are associated with cervical cancer encode E7 proteins with the highest affinity and the ability to degrade Rb (Munger, 2002).

Mutations In The Ube3a Gene

The UBE3A gene had been known to encode the E6-associated protein, a protein interacting with the human papilloma virus, to promote the nonlysosomal degradation of the p53 protein (Huibregtse et al., 1991 Scheffner et al., 1990). The gene encodes an E3 ubiquitin protein ligase that is probably involved in the ubiquitination of a diverse range of proteins (Scheffner et al., 1993 Huibregtse et al., 1993). The UBE3A gene encodes a member of a family of functionally related proteins defined by a conserved C-terminal 350- amino acid ''hect'' domain. Hect E3 proteins appear to be important in substrate recognition and in ubiquitin transfer. RT-PCR experiments provided evidence for several isoforms differing at their N termini. Each of the mRNAs was expressed in all cell lines tested. Additional 5' untranslated exons were also identified (Kishino and Wagstaff, 1998). In fact, at least 16 exons were identified, including six exons that encode the 5' UTR. The gene spans approximately 120 kb,...

Preclinical Vaccine Development

Fortunately, vaccine developers did not wait for the conclusions of the prospective epidemiology studies before initiating work on prophylactic HPV vaccines. Perhaps because these investigators were primarily laboratory-based researchers, and even, as in our case, involved in the studies of the HPV oncogenes, they were not unduly inhibited by the weak correlation between HPV infection and cervical disease seen in the early epidemiologic studies. In any event, considerable activity aimed toward developing HPV vaccines was underway by 1990. A vaccine based on a live attenuated HPV strain was not considered a viable option for two reasons. First, HPVs could not be propagated in replicating cells in culture, so there was no reasonable means of virus production. Second, the virus was known to contain at least three oncogenes, E5, E6, and E7, and a vaccine that delivered oncogenes might not be considered safe for general use as a prophylactic vaccine. Therefore, most efforts involved...

Posttranslational Modifications

P53 was first shown to be ubiquitinated by a cellular factor that associated with the viral E6 protein in papilloma-virus-infected cells (Scheffner et al., 1993). It was later determined to be predominantly degraded through the ubiquitin-proteosomal pathway (Chowdary et al., 1994 Maki et al., 1996). However, in normal cells Mdm2 (Hdm2 in humans hereafter referred to as Mdm2) acts as the predominant regulator of p53 protein levels by implementing its E3 ligase activity on p53 (Haupt et al., 1997 Honda et al., 1997 Kubbutat et al., 1997). Additionally, Mdm2 can inhibit the transactivation ability of p53 (Momand et al., 1992). Maintaining p53 at low levels is critical for cellular homeostasis in unstressed conditions. p53 assists in its

Antioncogenic Properties Of

The antitumor effects of AAV had been initially reported within a few years of identification of the virus itself when it was identified that infection of herpes simplex virus (HSV)-transformed hamster tumor cells with AAV delayed the appearance of palpable tumors and increased the survival time of the animals (70). Since then, several reports have confirmed the inhibition of viral oncogenesis by a variety of DNA viruses, including bovine papillomavirus-1 (71), human papillomavirus (HPV)-16 (72-74), and Epstein-Barr virus (75). Evidence from several reports also suggested that AAV infection might protect against human cervical cancer, in part, by interfering with HPV-induced tumori-genesis (76) although studies of Stickler et al. reported a lack of correlation of between AAV infection and cervical tumorigenesis in a Jamaican population (77).

Arrival Of Pml Cases And An Electron Microscope

Another interdisciplinary contact, which became of considerable importance later on, developed with Veterinary Science. In this Department, Dr. Carl Olson had created a research unit for the study of papilloma viruses, especially of bovine and canine types. A viral oncologist who appreciated the contributions of morphology, he early had acquired an electron microscope. My affiliation with Veterinary Science began in 1957. All such students had to do course work in pathology, and I became their instructor in neuropathology. Over the years I served on at least nine examination committees for M.S. or Ph.D. In May 1964, another of Dr. Olson's students took his Ph.D. examination, and I was a thesis reader. Among the illustrations for ''The Cytology of Canine Oral Papilloma'' were electron micrographs of cell nuclei with dispersed or aggregated virions. Listed among the references was Dr. Melnick's paper in Science (1962) entitled ''Papova Virus Group.'' In it, he combined the papil-loma...

The Start Of A Collaboration

Gabriele Zu Rhein clearly wanted to see this virus cultivated and characterized. She had demonstrated its presence in oligodendrocytes in PML brain tissue. The logical next step was to cultivate and identify it in order to study its role in nervous system disease. She wanted to have a part in that process, but she did not have the virology laboratory or virology background to do this, so she began prodding me to take it on in a collaborative project. I had a virology laboratory in the Department of Medical Microbiology in the same building but one floor below the Department of Pathology and Gabriele's electron microscope suite. Gabriele and I had co-authored a paper in 1956 concerned with a virus infection, but had not worked together in the interim. I had been studying persistent, chronic viral infections in cell cultures and animals and also was in the middle of a study of myxoma and fibroma virus infections. I had no experience with polyomaviruses, but I had some experience with...

The Association of HPV and Cancer

It has been known for many decades that filterable transmissible agents, i.e. viruses, cause cutaneous and mucosal papillomas (warts) in animal models and in humans 1 . The oncogenic potential of papillomaviruses was first demonstrated by Payton Rous and J.W. Beard in the 1930s. They observed that epidermal papillomas induced in domestic rabbits by Shope cottontail rabbit papillomavirus (CRPV) could progress to squamous cell carcinomas, and that viral oncogenicity was enhanced by chemical cocarcinogens. However, the progression of human common and genital warts to cancer was virtually never observed, and so a link between HPV infection and human carcinogenesis was largely discounted. However, there were indications, first noted in the mid-1800s by the Italian physician, Rigoni-Stern, that cervical cancer had the epidemiological characteristics of a sexually transmitted infection. He astutely noted that cervical cancer was common among prostitutes, but rare in virgins or nuns 2 . Much...

The Driving Force

Latent viruses associated with certain forms of cancer can also drive CD8+ T cells to senescence, as illustrated by the accumulation of CD8+CD28 T cells with reactivity to the human papilloma virus E7 antigen in cervical cancer patients (Pilch et al., 2002). Other viruses associated with chronic infection, such as Hepatitis C, also seem to elicit expanded populations of CD8+ T cells that lack CD28 expression (Kurokohchi et al., 2003). The common thread in all of these situations is chronic antigenic stimulation, which seems to result in massive cell division of antigen-reactive CD8+ T cells, ultimately causing them to reach what might be considered the endstage of their differentiation pathway, namely replicative senescence. Clearly, most memory T cells encounter their nominal antigen only once or twice over an individual's lifespan, and it is only those CD8+ T cells with reactivity to antigens that are never cleared from the body that have the potential to continue dividing...

Epithelial Membranes

The constant loss and renewal of cells is characteristic of epithelial membranes. The entire epidermis is completely replaced every 2 weeks the stomach lining is renewed every 2 to 3 days. Examination of the cells that are lost, or exfoliated, from the outer layer of epithelium lining the female reproductive tract is a common procedure in gynecology (as in the Pap smear).

DNA viruses

A number of groups, the hepadana viruses (hepatitis B), papilloma viruses (HPV) and herpes viruses (EBV) are associated with hepatocellular carcinoma, uterine cervical cancer, Burkitt's lymphoma and nasopharyngeal carcinoma, respectively. HPV have small double-stranded circular genomes of DNA which cause benign infective skin warts. They infect basal cells during their proliferative phase which on full differentiation complete the life cycle of the virus. Genital warts, the third commonest form of sexually transmitted disease, are also due to infection by HPV, and are associated with carcinoma of the cervix. Some 30 of all women are infected with HPV and DNA sequences from this have been identified in the majority of cervical carcinomas. Over 70 types of HPV are known to infect genital sites but only a few (predominately types 16 and 18) are associated with neoplasia. Cofactors are smoking, infection by herpes simplex virus and, possibly, oral...

Anal Cancer

Anal cancer is rare, accounting for less 5 of large-bowel tumours. Over 80 of anal cancers are squamous cell in origin, however, malignant melanoma may occur in the anal canal. The recognition of a high incidence of squamous cell carcinoma of the anus amongst some homosexual men led to the search for an infective aetiological agent. Risk factors for anal cancer include a history of genital warts and evidence now suggests an association between human papilloma virus types 16, 18, 30, 31 and 33, and anal cancer. It is believed that anal cancer may occur due to progression of anal intraepithelial neoplasia in a manner analogous to intraepithelial carcinoma of the cervix, vulva or vagina.

Nipple discharge

After clinical examination of the breast various investigations are undertaken. The discharge should be tested for the presence of blood (e.g. Labstix testing) and examined microscopically for the presence of malignant cells. All patients over the age of 35 years should also have mammography ultrasound examination of the breast may reveal the presence of dilated lactiferous ducts, particularly those close to the nipple and areola. In some patients, if there is discharge from a single duct, a ductogram (injection of contrast material into the duct) may demonstrate an intraduct papilloma, carcinoma or duct ectasia. In many women in whom no underlying cause for the discharge has been found, the discharge may resolve, be intermittent and or of small amount which does not concern the patient (see Fig. 17.16 for management). However, if there is a large amount of discharge, if it comes from a single duct or


The Food and Drug Administration (FDA) has recently approved the use of interferons to treat a number of diseases. Alpha interferon, for example, is now being used to treat hepatitis C, hairy-cell leukemia, virally induced genital warts, and Kaposi's sarcoma. The FDA has also approved the use of beta interferon to treat relapsing-remitting multiple sclerosis and the

Clinical Trials

In 2002, the results of the first proof of concept efficacy trial of an HPV VLP vaccine were published. Three 40 mg doses of Merck's HPV16 VLP in an aluminum adjuvant were administered over a 6-month period. Over the course of 1.5 years of follow up, 41 of the approximately 1,000 placebo controls developed persistent HPV16 infection, while none of the 1,000 VLP vaccines became persistently infected. Laura Koutsky's unannounced presentation of these results at the 2002 International Papillomavirus conference is etched in our memories. It was electrifying to hear that simple intramuscular injection of a VLP vaccine could induce 100 protection against persistent cervical infection, even in the short term. Two important decisions needed to be made before proceeding to large-scale phase III studies aimed at generating the data required for licensure. The first was the composition of the vaccine. In this instance, the development paths diverged for Merck and GSK, which, as noted above, had...


It is interesting to speculate why the efficacy of this vaccine has proven to be so high, while that of other STI vaccines have not. First, the vaccine is based on the production of neutralizing antibodies, not T cell effector responses, and antibody-mediated protection is a well-established principle on which to base a prophylactic viral vaccine. Second, strong neutralizing antibody responses are induced in greater than 99 of vaccinees. The mammalian immune system has clearly evolved to induce exceptionally strong antibody responses against the highly ordered and repetitive epitopes characteristically displayed on the surface of a VLP, presumably because virion neutralizing antibodies are so critical for defense against most viral infections. Third, papillomaviruses have a unique lifecycle that involves limited exposure of the virions to the systemic immune system. Therefore, there has been limited pressure on the virus to evolve mechanisms to escape systemic antibody responses...


Of keratinocyte and mammary epithelial cells (Neyns et al, 1999 Li et al, 2000). Although c-Jun overexpression in transgenic mice does not result in the development of tumors, c-Jun ablation or its inhibition suppresses tumor progression (Grigoriadis et al, 1993). c-Jun knockout mice have drastically reduced number and size of hepatic tumors (Eferl et al, 2003). c-Jun ablation in the skin of the tumor-prone K5-SOS-F transgenic mice results in less EGF receptor expression in basal keratinocytes and smaller papillomas, and transgenic mice expressing c-Jun TAM67 in the basal keratinocytes escape chemically induced papilloma development (Zenz et al, 2003 Young et al, 1999).


AAV vectors are also being examined as potential vehicles for tumor vaccines. In one study, an AAV-based tumor vaccine was developed by constructing a chimeric gene containing a human papillomavirus (HPV) type 16 E7 CTL epitope fused to a heat shock protein. When administered intramuscularly, this vaccine was able to eliminate tumor cells in synge-neic animals in a manner that was dependent on CD4+ and CD8+ cells. This suggests that vaccination with this gene could be a therapeutic treatment for cervical cancer containing HPV-16 E7 (295)


Although neoplasms are not a cause of acute or chronic pharyngitis, tumors arising in the oropharynx often present with signs and symptoms that most commonly indicate an infectious etiology. Patients treated for infectious pharyngitis, who do not improve, warrant further investigation to identify a possible neoplasm. Common presenting symptoms of oropharyngeal cancer include unilateral sore throat, dysphagia, odynophagia, weight loss, and otalgia. On physical exam, an asymmetric pharyngeal mass is the hallmark clinical finding and warrants further investigation (Fig. 4). The mass may be ulcerative, fungating, or mucosal covered and detectable only by palpation. Cervical adenopathy is present with advanced disease that has metastasized to the locoregional lymph nodes. Risk factors for oropharyngeal cancer include tobacco and alcohol abuse. The human papilloma virus has a role in a subset of oropharyngeal tumors.