文章：

宫颈HPV感染的自然史：未解决的问题

The natural history of cervical HPV infection: unresolved issues

原文发布日期：2007-01-01

DOI: 10.1038/nrc2050

类型: Review Article

开放获取: 否

要点：

1. The most frequently detected human papillomavirus (HPV) type at the time of diagnosis of squamous cell carcinoma (SCC) is HPV16, followed by HPV18. HPV18 is the type most strongly associated with adenocarcinoma of the cervix, which is increasing in incidence at the same time as the incidence of SCC is falling.
2. A bivalent HPV (types 16 and 18) and a quadrivalent HPV (types 6, 11, 16 and 18) vaccine are now being evaluated in phase III clinical trials, and have the potential to prevent about 70% of all cervical cancers. The quadrivalent HPV vaccine (Gardasil, Merck) has recently gained FDA and European Commission approval for use in women between the ages of 9–26.
3. Although most women will at some time be infected with HPV, very few will progress to invasive disease. The identification of more robust markers of disease progression requires a more complete understanding of the natural history of type-specific HPV infections.
4. It is unknown whether persistent HPV infections are characterized by the continuing detection of HPV, or by a state of viral latency during which the virus remains undetectable only to reappear later. A clearer understanding of these issues is essential for the effective implementation of screening strategies that include testing for HPV.
5. Integration of HPV into the host genome results in a loss of negative-feedback control of oncogene expression, following disruption of the viral regulatory early gene E2. Whether the integration event itself is crucial to carcinogenesis is the subject of continuing debate.
6. The prevalence of integrated forms varies with the infecting HPV type. Unlike HPV16, HPV18 integration seems virtually complete in women with cervical intraepithelial neoplasia grade 3 (CIN3) or invasive disease.
7. The association between viral load and cervical disease varies with the HPV type, the physical state of the virus and the heterogeneity of the cervical lesion. The complexity of these relationships indicates that a measurement of viral load is not clinically useful.
8. The concurrent or sequential detection of more than one HPV type is common. There is some evidence to indicate that the life cycles of different HPV types are not independent of each other, as has previously been assumed.
9. HPV oncogenes can activate the cellular methylation machinery. The pattern of HPV gene methylation varies with the viral life cycle, the presence of disease and possibly the HPV type.
10. Aberrant methylation of CpG islands in the promoter regions of tumour suppressor genes is one of several epigenetic changes that can contribute to carcinogenesis. The detection of these epigenetic changes in exfoliated cervical cells could improve the effectiveness of cervical screening programmes.

要点翻译：

1. 在诊断鳞状细胞癌（SCC）时，最常检测到的人乳头瘤病毒（HPV）类型是HPV16，其次是HPV18。HPV18与宫颈腺癌的关系最为密切，后者在发病率上升的同时，SCC的发病率却在下降。
2. 目前正在进行一种二价HPV（16型和18型）疫苗和一种四价HPV（6、11、16和18型）疫苗的三期临床试验，这些疫苗有望预防约70%的宫颈癌。四价HPV疫苗（Gardasil，默克公司）最近已获得美国食品药品监督管理局和欧盟委员会的批准，可用于9至26岁的女性。
3. 尽管大多数女性在某个时候会感染HPV，但很少有人会发展为浸润性疾病。要确定更可靠的疾病进展标志物，需要对类型特异性HPV感染的自然史有更全面的了解。
4. 目前尚不清楚持续性HPV感染的特征是持续检测到HPV，还是病毒处于潜伏状态，在此期间病毒无法检测到，只在之后重新出现。更清晰地理解这些问题对于有效实施包括HPV检测在内的筛查策略至关重要。
5. HPV整合到宿主基因组后，随着病毒调控早期基因E2的破坏，会导致癌基因表达的负反馈控制丧失。整合事件本身是否对致癌作用至关重要，目前仍在持续争论中。
6. 整合形式的流行率因感染的HPV类型而异。与HPV16不同，在宫颈上皮内瘤变3级（CIN3）或浸润性疾病的女性中，HPV18的整合几乎完全发生。
7. 病毒载量与宫颈疾病之间的关联因HPV类型、病毒的物理状态以及宫颈病变的异质性而异。这些关系的复杂性表明，病毒载量的测量在临床上并无实用价值。
8. 同时或顺序检测到多种HPV类型的情况很常见。有一些证据表明，不同HPV类型的生命周期并非如先前假设的那样相互独立。
9. HPV癌基因可以激活细胞甲基化机制。HPV基因甲基化的模式因病毒生命周期、疾病的存在以及可能的HPV类型而异。
10. 肿瘤抑制基因启动子区域CpG岛的异常甲基化是几种可能促进致癌作用的表观遗传变化之一。在脱落的宫颈细胞中检测这些表观遗传变化可能会提高宫颈筛查项目的有效性。

英文摘要：

The identification of high-risk human papillomavirus (HPV) types as a necessary cause of cervical cancer offers the prospect of effective primary prevention and the possibility of improving the efficiency of cervical screening programmes. However, for these opportunities to be realized, a more complete understanding of the natural history of HPV infection, and its relationship to the development of epithelial abnormalities of the cervix, is required. We discuss areas of uncertainty, and their possible effect on disease prevention strategies.

摘要翻译： 

高危型人乳头瘤病毒（HPV）被确认为宫颈癌发生的必要病因，为有效的一级预防提供了前景，并有望提高宫颈癌筛查项目的效率。然而，要实现这些机遇，需要更全面地了解HPV感染的自然史及其与宫颈上皮异常发生的关系。我们讨论了其中存在的不确定性领域，以及这些不确定性可能对疾病预防策略产生的影响。

原文链接：

The natural history of cervical HPV infection: unresolved issues