HUMAN PAPILLOMAVIRUS EXPRESSION AND ANTIGENICITY

有明确的证据表明，肛门生殖器瘤的发展的第一步是感染高危人乳头瘤病毒（HPV），但也很清楚，病毒、宿主和环境因素的相互作用决定了哪些感染将发展为恶性肿瘤。研究发现，一部分女性会患上一种以上的肛门生殖器癌症，这一发现为关注风险因素影响可能最为显著的群体提供了机会。这个项目的目标是调查的病毒和免疫因素，有助于单一和多重肛门生殖器恶性肿瘤。有3个具体目的：1)确定特定的HPV类型是否更频繁地与多种肿瘤相关，并确定非原型样（NPL）变异是否更普遍，这种变异已被证明是前体病变发展的危险因素，在多种或单一的肛门生殖器癌症病例中更为普遍。鉴定病毒类型和变异，结合整合位点研究，将区分多发原发性器官肿瘤与复发。2) HPV VLPs的血清抗体是目前宿主对HPV感染免疫反应的最佳标志物，其产生是预防性疫苗的目标。我们建议描述与HPV衣壳蛋白血清阳性相关的危险因素，用表位变异绘制表位；3)确定热HLA基因型是否在单个或多个恶性肿瘤的进展中起作用。对宫颈鳞状细胞癌病例对照系列II类等位基因的分析发现BRB1*1001和DRB1*1101有显著相关性。这些等位基因加上DRB1*04和DRB1*07在HPV 16肿瘤病例中发现了显著的相关性，并且这种相关性不仅仅与其他HPV相关的恶性肿瘤（如外阴癌和子宫颈腺癌）中是否存在相同的相关性有关。后者也将使我们能够确定HPV 18肿瘤是否与不同的等位基因相关。最后，我们将分析浸润性SCC子宫颈组的I类基因。结合肿瘤组织中HPV DNA类型和变异、血清学特征和HLA基因型的数据，应该有助于阐明影响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.