HPV VLP AND ANTIGEN PRESENTING CELLS

描述(申请人提供)：持续的高风险人乳头瘤病毒(HPV)感染，与HPV16一样，与宫颈癌和其他几种癌症的发展有关。HPV病毒家族建立了持续性感染，因为它进化出了使其能够逃避人类免疫系统的机制。这项研究的长期目标是了解HPV是如何逃避免疫系统的，以便找到治疗HPV感染和相关疾病的新方法。HPV逃避免疫的潜在机制之一是在没有郎格汉斯细胞(LC)共刺激的情况下通过抗原提呈诱导耐受，朗格汉斯细胞是HPV感染部位的抗原提呈细胞。初步数据表明，L2小衣壳蛋白可能通过与LC上的特定受体相互作用而介导免疫逃逸，从而抑制LC的成熟，并可能通过Toll样受体(TLR)激动剂激活HPV暴露的LC。然而，目前尚不清楚这些TLR激动剂是否足以克服HPV暴露的LC对T细胞的抑制作用，并诱导HPV特异性T细胞反应。我们假设：1)为了逃避T细胞免疫，HPV16 L2通过与细胞表面受体ANXA2的相互作用抑制LC的成熟；2)免疫调节化合物的使用将能够逆转宫颈上皮内瘤变(CIN)患者HPV暴露的LC的免疫抑制表型和功能，并诱导HPV特异性T细胞的激活。为了解决这些假说，将探索以下目标：1)确定HPV16L2是否通过与ANXA2的相互作用而抑制LC的成熟。目的2)确定人乳头瘤病毒16型(HPV16)感染的LC是否耐受T细胞。目的3)探讨免疫调节剂能否逆转HPV16感染的CIN患者LC的免疫抑制表型和功能。目的4)确定除HPV16外，其他高危型、低危型和疣状型HPV是否也抑制LC成熟。将对这些目标进行调查，以更详细地了解HPV如何通过与LC的相互作用介导免疫逃逸，并定义有可能抑制或逆转免疫逃逸的化合物。在不久的将来，这种机制研究可能会导致在临床试验中识别出要测试的化合物，目标是清除持续的HPV感染，从而降低患上更严重疾病的风险，如宫颈癌和其他与HPV相关的癌症。1 公共卫生相关性：人乳头瘤病毒(HPV)是一个重大的公共卫生问题，因为它广泛传播，持续存在，导致多种疾病，而预防性疫苗并不能消除现有的HPV感染。这个项目的成功完成将有助于理解为什么免疫系统无法清除HPV感染，并制定战略，加快受感染妇女的病毒清除，从而防止HPV引起的损害，包括癌症。

DESCRIPTION (provided by applicant): Persistent high-risk human papillomavirus (HPV) infection, like that of HPV16, is linked to the development of cervical and several other cancers. The HPV family of viruses establishes persistent infections because it has evolved mechanisms that allow it to evade the human immune system. The long-term goal of this study is to understand how HPV evades the immune system in order to find new ways to treat HPV infection and associated diseases. One of the potential mechanisms by which HPV escapes immunity is inducing tolerance via antigen presentation in the absence of co-stimulation by Langerhans cells (LC), the antigen-presenting cells at the site of HPV infections. Preliminary data shown here suggest that the L2 minor capsid protein may mediate immune escape by interacting with a specific receptor on LC thereby suppressing the maturation of LC and that it may be possible to activate HPV-exposed LC with Toll-like receptor (TLR) agonists. However it is unknown whether these TLR agonists will be potent enough to overcome the suppressive effects of HPV-exposed LC on T cells and induce HPV-specific T cell responses. We hypothesize that: 1) To escape T cell immunity, HPV16 L2 suppresses the maturation of LC through interaction with the cell surface receptor ANXA2; and 2) The use of immune-modulating compounds will enable reversal of the immune-suppressive phenotype and function of HPV-exposed LC from cervical intraepithelial neoplasia (CIN) patients, and induce activation of HPV-specific T cells. To address these hypotheses, the following aims will be explored: Aim 1) Determine whether HPV16 L2 is responsible for suppressing the maturation of LC through interaction with ANXA2. Aim 2) Determine whether HPV16-exposed LC tolerize T cells. Aim 3) Investigate whether immune-modulating compounds can reverse the immune- suppressive phenotype and function of HPV16-exposed LC from CIN patients. Aim 4) Determine whether, apart from HPV16, other high-risk, low-risk and wart type HPV also suppress LC maturation. These aims will be investigated to get a more detailed understanding of how HPV mediates immune escape via interactions with LC and define compounds that have the potential to inhibit or reverse it. In the near future, this mechanistic research could lead to the identification of compounds for testing in clinical trials, with the goal of clearing persistent HPV infection and therefore reducing risk of developing more serious disease such as cervical and other HPV-associated cancers. 1 PUBLIC HEALTH RELEVANCE: Human papillomavirus (HPV) is a significant public health problem because it is wide-spread, persists, causes several diseases, and the preventive vaccine does not eliminate existing HPV infection. Successful completion of this project will lead to an understanding of why the immune system fails to clear HPV infections and the development of strategies to expedite viral clearance in infected women, thereby preventing HPV-induced lesions including cancer.