HPV对生殖系统影响的研究进展

人乳头瘤病毒（HPV）感染可引发生殖系统的疣变以及恶性肿瘤.其中高危型HPV的感染导致了约70%的女性宫颈癌.HPV病毒蛋白可通过调节细胞基因组的稳定性、转录活性、泛素化途径和细胞代谢等机制诱发癌症.同时HPV的持续慢性感染和免疫应答的紊乱也与宫颈癌的发生相关.本文对HPV感染对生殖系统健康的影响、HPV病毒分子结构、HPV病毒蛋白的致癌的机制以及宿主对于HPV感染的免疫应答的近期研究进展进行了综述,并总结展望了HPV相关生殖系统疾病的预防和治疗的前景.     

Molecular events in uterine cervical cancer

OBJECTIVE: To review the literature regarding the molecular events which occur in the development of uterine cervical cancer, with particular reference to human papillomavirus (HPV) infection. METHODOLOGY: Bibliographic searches of Medline and the ISI citation databases using appropriate keywords, including the following: papillomavirus, cervix, pathology, cyclin, chromosome, heterozygosity, telomerase, smoking, hormones, HLA, immune response, HIV, HSV, EBV. CONCLUSIONS: It has become clear that most cervical neoplasia, whether intraepithelial or invasive, is attributable in part to HPV infection. However, HPV infection alone is not sufficient, and, in a small proportion of cases, may not be necessary for malignant transformation. There is increasing evidence that HPV gene products interfere with cell cycle control leading to secondary accumulation of small and large scale genetic abnormalities. This may explain the association of viral persistence with lesion progression but, in many patients, secondary factors, such as smoking and immune response, are clearly important. However, the mechanisms involved in the interaction between HPV and host factors are poorly understood.


     

Ubiquitination in host immune response to human papillomavirus infection

Human papillomavirus (HPV) infection with low-risk or high-risk subtypes is very common. Infection with HPVs is often a major causative factor for the development of cutaneous benign lesions, cervical cancer, and a number of other tumors. The mechanisms of host immunity to prevent and control HPV infection still remain unclear. The importance of ubiquitination (or ubiquitylation) as an intracellular proteasomal-mediated protein degradation pathway, and as an important modulator for the regulation of many fundamental cellular processes has been valued over the last decade. Although the molecular and cellular mechanisms are not completely established, the critical role of ubiquitination in host immune response to HPV infection has become increasingly apparent. This review summarizes current knowledge on the possible role that ubiquitination plays in regulating the host immune response during HPV infection. Targeting the components of the ubiquitin system might offer potential therapeutic strategies for HPV-related diseases in the future.     

HPV und Neoplasien der Haut

Human papillomaviruses (HPV) induce benign and malignant tumors of skin and mucosa. Non-melanoma skin cancer (NMSC) is the most frequent malignancy in fair-skinned populations, particularly frequent in countries with high sun exposure and in immunosuppressed patients. The high prevalence of Beta-HPV in skin tumors renewed interest in a possible etiologic role of HPV. In contrast to cervical cancer, the presence of HPV is probably not mandatory for maintenance of the malignant phenotype of skin cancer cells, since only low copy numbers of HPV DNA persist in skin cancers. Higher viral loads in actinic keratoses are compatible with a carcinogenic role of cutaneous HPV in early phases of NMSC development. There is some evidence from case-control studies for an increased risk of cutaneous squamous cell carcinoma related to beta-HPV infection. HPV8 is clearly carcinogenic in transgenic mice. At the molecular level, oncogenic activities of beta-HPV have been attributed to effective inhibition of apoptosis and interference with DNA repair pathways by viral E6 proteins. In addition E7 proteins deregulate the cell cycle and enhance invasive growth.     

The oncogenic potential of human papillomaviruses: a review on the role of host genetics and environmental cofactors

Human papillomaviruses (HPVs), with over 100 genotypes, are a very complex group of human pathogenic viruses. In most cases, HPV infection results in benign epithelial proliferations (verrucae). However, oncogenic types of HPV may induce malignant transformation in the presence of cofactors. For example, over 99% of all cervical cancers and a majority of vulval, vaginal, anal and penile cancers are the result of oncogenic HPV types. Such HPV types have been increasingly linked to other epithelial cancers involving the skin, larynx and oesophagus. Although viral infection is necessary for neoplastic transformation, evidence suggests that host and environmental cofactors are also required. Research investigating HPV oncogenesis is complex and quite extensive. The inability to produce mature HPV virions in animal models has been a major limitation in fully elucidating the oncogenic potential and role of associated cofactors in promoting malignant transformation in HPV-infected cells. We have reviewed the literature and provide a brief account of the current understanding of HPV oncogenesis, emphasizing the role of genetic susceptibility, immune response, and environmental and infectious cofactors.     

New viral vaccines for dermatologic disease

Two new viral vaccines have recently been approved by the Food and Drug Administration. Human papillomavirus (HPV) vaccine is intended to reduce infection with the most common HPV types that cause anogenital disease, including cervical cancer and genital warts. Herpes zoster (HZ) vaccine is intended to prevent shingles and its complications. The use of these two vaccines will immediately begin to impact dermatologic practice throughout the world and will reduce the healthcare burden associated with the diseases caused by the two viruses. The following review summarizes the relevant pathophysiology and epidemiology of genital warts, cervical neoplasia, and herpes zoster and describes the recent trials that have demonstrated efficacy and safety of the HPV and HZ vaccines. LEARNING OBJECTIVES: Following the completion of this learning activity, the participant will be able to describe the mechanisms of HPV and varicella zoster virus infection as well as pathogenesis, identify key aspects of the immune system involved in clearing the infection, and prescribe HPV and HZ vaccines for prevention of disease.     

HPV vaccine update: new indications and controversies

Human papillomavirus (HPV) has a predilection for infecting epidermal and mucosal surfaces such as those of the anogenital region. HPV causes substantial pre-malignant, malignant, and benign disease in both women and men, ranging from cervical, vulvar, penile, and anal cancers to condyloma acuminata (genital warts). Although HPV vaccination is becoming more common, infection rates remain high in both genders. Perception of HPV vaccine has largely centered on its ability to prevent cervical cancer in women, though indication for its use in men is expanding. The benefits to men include prevention of genital warts and, more recently, regulatory approval was expanded in the US for prevention of anal cancer. Herein, we review HPV vaccine with a focus on its new indication in men and existing controversies.     

Humoral and cellular immune response in HPV vaccination

Human papillomaviruses (HPV) infect skin or mucosal epithelia causing warts and dysplasia. Infections with certain high-risk HPV types in the anogenital tract can lead to malignant transformation. Cervical cancer is the second most common malignant disease in young women responsible for 275000 deaths annually worldwide. More than 50% of sexually active people acquire HPV infections over their lifetime. Around 80% of infections remain subclinical and are cleared by the immune system. Recently prophylactic vaccines against the two most common high-risk types HPV16 and 18, and additionally low-risk types HPV6 and 11, respectively, have become available. We present an overview concerning recent knowledge on natural and vaccine-induced immunity against HPV infections.     

Humorale und zelluläre Immunantwort im Rahmen der HPV-Impfung

Human papillomaviruses (HPV) infect skin or mucosal epithelia causing warts and dysplasia. Infections with certain high-risk HPV types in the anogenital tract can lead to malignant transformation. Cervical cancer is the second most common malignant disease in young women responsible for 275000 deaths annually worldwide. More than 50% of sexually active people acquire HPV infections over their lifetime. Around 80% of infections remain subclinical and are cleared by the immune system. Recently prophylactic vaccines against the two most common high-risk types HPV16 and 18, and additionally low-risk types HPV6 and 11, respectively, have become available. We present an overview concerning recent knowledge on natural and vaccine-induced immunity against HPV infections.     

高危型人乳头瘤病毒检测在子宫颈癌筛查中的临床应用效果研究

目的:探讨人乳头瘤病毒及行为危险因素与子宫颈癌的临床关系。方法:通过分析2014年6月至2015年6月医院收治的203例HPV感染患者的临床资料,对患者临床资料进行整合,探讨HPV感染及相关行为危险因素及其同子宫颈癌的相关关系。结果:HPV感染并发宫颈癌患者中高危HPV患者占比显著高于低危HPV感染患者,比较差异有统计学意义(P0.05);两组患者行为危险因素中吸烟、首次性行为年龄、性伴侣个数、性卫生意识、孕次和避孕方式相关因素指标存在显著差异,有统计学意义(P0.05)。结论:高危型HPV感染是诱发子宫颈癌的高危因素,性行为及吸烟等行为危险因素同子宫颈癌发病有一定的相关性。     

Human papillomavirus infection in Danish female sex workers. Decreasing prevalence with age despite continuously high sexual activity

BACKGROUND: The prevalence of the human papillomavirus (HPV) has been found to decrease with age, but whether this applies to all populations is not clear. Knowledge about the generalizability of this age dependency is important to understand the natural history of the infection, but may also have implications in relation to the use of HPV testing in cervical cancer screening. GOAL: To study the prevalence and risk factors for HPV infection in a selected population of female sex workers and to compare the results with persons with different sexual habits from two other populations in the same geographic area. STUDY DESIGN: A case-control study among 188 female sex workers from Copenhagen. Data were obtained by personal interviews. Cervical material was collected by a self-administered lavage kit, and HPV testing was done by means of GP5+/6+ primers based on HPV, polymerase chain reaction, enzyme immunoassay. RESULTS: Among sex workers, age was the most important risk factor for HPV infection. Number of private sex partners in the last 4 months was also a significant risk factor, and a protective effect of condom use was indicated. CONCLUSION: The HPV prevalence is declining in sex workers with age despite continuously high sexual activity, most likely indicating that an immune response is acquired over time.     

Screening HIV-infected women for cervical cancer in Thailand: findings from a demonstration project

OBJECTIVES: Although cervical cancer is an AIDS-defining illness, few HIV-infected women are routinely screened for cervical cancer in Thailand. We screened HIV-infected women for cervical cancer as a component of HIV care and assessed high-risk human papillomavirus (HPV) and cervical cancer prevalence. METHODS: From July 2003 through February 2004, HIV-infected women attending either an infectious disease clinic or a sexually transmitted infection (STI) clinic in Bangkok were tested for high-risk HPV types by Hybrid Capture 2 and screened for cervical cancer by Pap test; those with abnormal cervical cytology were referred for diagnosis and treatment. RESULTS: Two hundred ten HIV-infected women at an infectious disease clinic (n = 150) and an STI clinic (n = 60) received cervical cancer screening. The high-risk HPV prevalence was 38.6% and the prevalence of abnormal cervical cytology was 20.4%. Abnormal cervical cytology and high-risk HPV detection were associated (P < 0.001). We received pathology reports for 23 (53.5%) of 43 women, including all those with a Pap test showing high-grade squamous intraepithelial lesions; the cervical cancer prevalence was 1.9% (4 of 210; 95% confidence interval, 0.5-4.8%). CONCLUSION: The estimated prevalence of high-risk HPV and cervical cancer among HIV-infected women in Thailand was high. This emphasizes the need to integrate cervical cancer screening into HIV care.     

Human papilloma virus vaccines: Current scenario

Genital human papillomavirus (HPV) infection is the most common sexually transmitted infection with an estimated worldwide prevalence of 9-13% and approximately 6 million people being infected each year. Mostly acquired during adolescence or young adulthood, HPV presents clinically as anogenital warts and may progress to precancerous lesions and cancers of the cervix, vagina, vulva, penis and anus, and oropharynx. HPV infection is considered to contribute to almost 100% cervical cancers and at least 80% of anal and 40-60% of vulvar, vaginal, and penile cancers. At present, two prophylactic HPV vaccines are commercially available and both are prepared from purified L1 structural proteins. These proteins self-assemble to form virus-like particles that induce a protective immunity. Gardasil(?) is a quadrivalent vaccine against HPV types 6, 11, 16, and 18 and is recommended for use in females 9-26 years of age, for the prevention of cervical, vulvar, and vaginal cancers and intraepithelial neoplasia and condyloma acuminata and recently for vaccination in boys and men 9-26 years of age for the prevention of genital warts. Cervarix? is a bivalent vaccine approved for the prevention of cervical cancer and precancerous lesions caused by HPV 16 and 18, in females 10-25 years. HPV vaccines are safe and efficacious against type-specific HPV-induced anogenital warts, precancerous lesions, and cervical cancer. The vaccines are most effective when given before the onset of sexual activity and provide long-term protection. Effective vaccination coverage in young adolescent females will substantially reduce the incidence of these anogenital malignancy-related morbidity and mortality. There is need to generate India-specific data on HPV epidemiology and HPV vaccination efficacy as well as continue worldwide surveillance and development of newer vaccines.     

Human papillomavirus–associated diseases

The human papillomavirus (HPV) may be associated with various oral, genital, and cutaneous conditions, both benign and malignant. The association between sexually transmitted α-HPV types is the strongest with cervical cancer because almost all such malignancies contain viral DNA, notably HPV types 16 and 18. The contribution of cancer causing HPV types in other anogenital, oral, and oropharyngeal malignancies, plus benign disorders, is lower and with a less significant public health concern. Cervical cytologic screening is a well-established preventive measure that allows early detection and successful treatment of precancerous cervical lesions. In cases of all other HPV-associated disorders, early detection of a precancerous lesion is either difficult or almost impossible. HPV vaccination remains the only preventive measure against most HPV-related diseases.     

Toll样受体与HPV感染相关疾病研究进展

人乳头瘤病毒感染引起皮肤、黏膜疣状增生,且与宫颈癌等恶性肿瘤的发生密切相关.Toll样受体能特异性识别微生物病原相关分子模式,启动天然免疫应答并激活获得性免疫反应.研究表明,某些Toll样受体在人乳头瘤病毒感染宿主表达异常,Toll样受体激动剂对人乳头瘤病毒感染相关疾病具有治疗作用.概述Toll样受体及其与人乳头瘤病毒感染相关疾病的关系以及Toll样受体激动剂在人乳头瘤病毒感染相关疾病治疗中的研究现状.     

Tissue effects of and host response to human papillomavirus infection.

Human papillomaviruses are a heterogeneous group of DNA tumor viruses associated with hyperplastic (warts, condylomata), dysplastic (CIN and VIN), and malignant lesions (carcinomas) of squamous epithelium. Each HPV type is preferentially associated with specific clinical lesions and has an anatomic site preference for either cutaneous or mucosal squamous epithelium. Infection appears to begin in the basal cells. Early gene expression is associated with acanthosis, and late gene expression is associated with appearance of structural antigens and virions in nuclei of cells of the granular layer, usually koilocytotic cells. Malignant transformation of warts and papillomas appears to be related to a variety of factors: (1) infection by certain HPV types (HPV-5, HPV-8, HPV-16, HPV-18, HPV-31); (2) decreased cellular immunity to HPV-associated antigens; and (3) interaction with cofactors such as other microorganisms or sunlight. Spontaneous regression or successful treatment of the benign lesions appears to depend on either naturally acquired or iatrogenically related stimulation of HPV type-specific immunity. The humoral antibody response to HPV particles may be important in preventing infection. In contrast, the local events surrounding regression of warts and condylomata are primarily associated with specific cell-mediated immunity. Local cell-mediated immune responses, particularly cell-associated soluble mediators and stationary macrophage-like cells, may be especially important in the host's immune response to mucosal infections.     

高危型人乳头状瘤病毒分型检测在宫颈癌及癌前病变中的价值研究

目的:评价高危型人乳头状瘤病毒HPV16,HPV18检测在宫颈癌及癌前病变筛查中的应用价值。方法:以宫颈组织病理学诊断为金标准,采用荧光PCR技术检测筛查360例病例的HPV16,HPV18分型情况,并分别通过传统细胞涂片和液基细胞学法进行验证,比较筛查方法的灵敏性和特异性指标,同时了解永川地区HPV16和HPV18的感染率,评价检测意义。结果:HPV16或HPV18总感染率为41.4%(149/360)。其中HPV16,HPV18阳性率分别为62.4%(93/149)和32.2%(48/149),混合感染率为6%(9/149)。HPV16和HPV18分型的检测方法的灵敏度,特异度,阴性预测值和阳性预测值均高于传统细胞涂片和液基细胞学法,且HPV检测联合液基细胞筛查效能高于联合传统细胞学涂片法。结论:高危型HPV16,HPV18的感染与宫颈癌及宫颈癌前病变密切相关,HPV16,HPV18的检测对筛查、预防宫颈癌,降低宫颈癌发病率有重要作用。     

徐州地区人乳头瘤病毒感染及病毒分型与宫颈病变的关系

目的了解徐州及其周边地区女性生殖道人乳头瘤病毒(HPV)分型感染的情况,分析HPV基因分型检测对宫颈疾病的实际诊断价值,为宫颈病变的防治与临床诊断提供可靠依据。方法选择2016年12月至2017年11月在徐州市中心医院体检并进行HPV分型检测的13 755例女性患者为研究对象,其中468例女性患者经过病理诊断确诊为宫颈病变,对其完成了阴道脱落细胞液基细胞学检查(TCT)和阴道镜下组织病理学检查,以病理诊断为宫颈病变诊断的"金标准",分析高危型HPV感染与宫颈病变的关系。结果在13 755例女性患者中,HPV阳性2 752例,阳性率20.0%;21种HPV亚型均被检出。高危型HPV亚型感染中,HPV16、52、53、58、56五种亚型最为常见;其中单一感染2 020例,占阳性患者的73.4%,多重感染732例,占阳性患者的26.6%;感染的高峰年龄为≤20岁组,随着年龄增长,HPV感染率逐渐下降,>50岁组为第二个高峰。随着宫颈病变程度的增加,HPV高危型感染阳性率呈现逐渐升高的趋势。结论徐州及周边地区女性HPV基因型的分布具有明显的年龄和区域分布特异性。HPV分型检测筛查宫颈病变敏感性和阴性预测值高。     

Prophylaktische HPV-Impfstoffe

The prophylactic HPV vaccines consist of virus-like particles (VLP) of HPV 16 and 18 produced by recombinant DNA technology. These viruses induce about 70% of the worldwide occurring cases of cervical cancer as well as a substantial fraction of malignant tumors of the vulva, penis, perianum and oropharynx. One of the vaccines contains in addition VLPs of HPV 6 and 11 for prevention of genital warts (condylomata acuminata). In clinical trials with up to 6.4 years of follow-up the vaccines demonstrated an efficacy of almost 100% against infection by HPV 16 and 18 and the high-grade intraepithelial lesions (CIN, VIN, VaIN) they induce. Most likely due to cross-neutralizing antibodies one of the vaccines also protects significantly against lesions that are induced by genetically related non-vaccine types. Prevention of cases of cervical cancer will only be realized about 10 years after introduction of the vaccine in populations-based trials. First success of a vaccination campaign was already appreciated in Australia by reduction of the incidence of genital warts. Vaccinating males is a reasonable means to reduce the risk of infection in women but also provides to them a direct benefit through the recently documented efficacy of the quadrivalent vaccine against genital warts.