HUMAN PAPILLOMAVIRUS EXPRESSION AND ANTIGENICITY

有明确的证据表明，肛门生殖道肿瘤发展的第一步是感染高危人乳头瘤病毒(HPV)，但也很明显，病毒、宿主和环境因素的相互作用决定了哪些感染将进展为恶性肿瘤。一组女性患上不止一种肛门癌，这一发现提供了一个机会，可以专注于风险因素可能影响最显著的群体。这个项目的目标是调查病毒和免疫学因素对单发和多发肛门恶性肿瘤的影响。有三个具体的目标：1)确定特定的HPV类型是否更频繁地与多个肿瘤相关，以及确定已被证明是发展先兆病变的危险因素的非原型样变异体是否在多个或单个肛门生殖道癌中更普遍。确定病毒类型和变异的特征，结合整合部位的研究，将区分多个原发肛门肿瘤和复发。2)血清抗HPV VLP抗体是目前最能反映机体对HPV感染的免疫应答的标志物，其产生是预防性疫苗研究的目标。我们建议表征与HPV衣壳蛋白血清阳性相关的危险因素，用表位变异来绘制表位图；以及3)确定热的HLA型在单个或多个恶性肿瘤的进展中起作用。对宫颈鳞癌病例对照系列中II类等位基因的分析发现，BRB1*1001和DRB1*1101有显著的相关性。这些等位基因加上DRB1*04和DRB1*07在HPV16肿瘤的病例中被发现存在显著的关联，而且这种关联不仅仅与其他HPV相关的恶性肿瘤，如外阴和子宫腺癌是否存在相同的关联有关。后者还将使我们能够确定HPV18肿瘤是否与不同的等位基因有关。最后，我们将对侵袭性宫颈鳞癌组织中的I类基因进行分析。结合肿瘤组织中HPV DNA类型和变异、血清学特征和人类白细胞抗原基因分型，应有助于阐明影响HPV相关恶性肿瘤进展的病毒学和免疫学因素。

There is unambiguous evidence that an initial step in the development of anogenital neoplasia is infection with high risk human papilomaviruses (HPV), however it is also clear that an interplay of viral, host and environmental factors determine which infections will progress to malignancy. The finding that a subset of women develop more than one anogenital cancer provides an opportunity to focus on a group where the affect of the risk factors may be the most striking. The goal of this project is to investigate the viral and immunologic factors that contribute to single and multiple anogenital malignancies. There are 3 specific aims: 1) to determine whether specific HPV types are more frequently associated with multiple tumors, and to determine whether non-prototype-like (NPL) variants, that have been shown to be a risk factor for development of precursor lesions, are more prevalent in cases of multiple or single anogenital cancers. Characterizing the viral types and variants will, in combination with integration site studies distinguish multiple primary anogenital tumors vs. recurrence. 2) Serum antibodies to HPV VLPs are currently the best marker of the host immune response to HPV infection, and their generation is the goal of prophylactic vaccines. We propose to characterize the risk factors associated with seropositivity to HPV capsid proteins, to map the epitopes with epitope-variants; and 3) to determine whether the hot HLA genotype plays a role in progression to single or multiple malignancies. Analysis of the class II alleles in a case control series of squamous cell carcinoma of the cervix found significant associations for BRB1*1001 and DRB1*1101. Striking associations for those alleles plus DRB1*04 and DRB1*07 were seen for cases with HPV 16 tumors, and the associations were not related simply to whether the same associations are seen in other HPV-associated malignancies such as vulvar and adenocarcinoma of the cervix. The latter will also allow us to determine whether HPV 18-tumors are associated with different alleles. Finally, we will analyze the class I genes in the invasive SCC cervix groups. The combination of data on the HPV DNA type and variant in tumor tissue, the serologic profiles and the HLA genotypes should help clarify virologic and immunologic factors that influence the progression of HPV associated malignancies.