Middleton Kate, Peh Woei, Southern Shirley, Griffin Heather, Sotlar Karl, Nakahara Tomomi, El-Sherif Amira, Morris Lesley, Seth Rashmi, Hibma Merilyn, Jenkins David, Lambert Paul, Coleman Nicholas, Doorbar John
National Institute for Medical Research, Mill Hill, London.
J Virol. 2003 Oct;77(19):10186-201. doi: 10.1128/jvi.77.19.10186-10201.2003.
The productive cycle of human papillomaviruses (HPVs) can be divided into discrete phases. Cell proliferation and episomal maintenance in the lower epithelial layers are followed by genome amplification and the expression of capsid proteins. These events, which occur in all productive infections, can be distinguished by using antibodies to viral gene products or to surrogate markers of their expression. Here we have compared precancerous lesions caused by HPV type 16 (HPV16) with lesions caused by HPV types that are not generally associated with human cancer. These include HPV2 and HPV11, which are related to HPV16 (supergroup A), as well as HPV1 and HPV65, which are evolutionarily divergent (supergroups E and B). HPV16-induced low-grade squamous intraepithelial lesions (CIN1) are productive infections which resemble those caused by other HPV types. During progression to cancer, however, the activation of late events is delayed, and the thickness of the proliferative compartment is progressively increased. In many HPV16-induced high-grade squamous intraepithelial lesions (CIN3), late events are restricted to small areas close to the epithelial surface. Such heterogeneity in the organization of the productive cycle was seen only in lesions caused by HPV16 and was not apparent when lesions caused by other HPV types were compared. By contrast, the order in which events in the productive cycle were initiated was invariant and did not depend on the infecting HPV type or the severity of disease. The distribution of viral gene products in the infected cervix depends on the extent to which the virus can complete its productive cycle, which in turn reflects the severity of cervical neoplasia. It appears from our work that the presence of such proteins in cells at the epithelial surface allows the severity of the underlying disease to be predicted and that markers of viral gene expression may improve cervical screening.
人乳头瘤病毒（HPV）的生产周期可分为不同阶段。在下位上皮层中，细胞增殖和游离型维持之后是基因组扩增和衣壳蛋白的表达。这些在所有生产性感染中都会发生的事件，可以通过使用针对病毒基因产物或其表达替代标志物的抗体来区分。在这里，我们比较了由16型HPV（HPV16）引起的癌前病变与由通常不与人类癌症相关的HPV类型引起的病变。这些包括与HPV16相关的HPV2和HPV11（A超群），以及在进化上不同的HPV1和HPV65（E和B超群）。HPV16诱导的低度鳞状上皮内病变（CIN1）是生产性感染，类似于由其他HPV类型引起的感染。然而，在进展为癌症的过程中，晚期事件的激活被延迟，增殖区的厚度逐渐增加。在许多HPV16诱导的高度鳞状上皮内病变（CIN3）中，晚期事件仅限于靠近上皮表面的小区域。生产周期组织中的这种异质性仅在由HPV16引起的病变中可见，在比较由其他HPV类型引起的病变时并不明显。相比之下，生产周期中事件启动的顺序是不变的，并且不取决于感染的HPV类型或疾病的严重程度。病毒基因产物在受感染子宫颈中的分布取决于病毒能够完成其生产周期的程度，这反过来又反映了宫颈肿瘤形成的严重程度。从我们的工作中可以看出，上皮表面细胞中此类蛋白质的存在有助于预测潜在疾病的严重程度，并且病毒基因表达的标志物可能会改善宫颈癌筛查。
