Exploration of novel pan-HPV treatments to block development of AIDS-associated c

探索新型泛 HPV 治疗方法以阻止艾滋病相关疾病的发展

• 批准号: 7944126
• 负责人: WIJBE MARTIN KAST
• 金额: $ 50万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-29 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7944126
• 关键词: AIDS therapy; ANXA2 gene; Address; Agonist; Anogenital cancer; Antigen Presentation; Antigen-Presenting Cells; Anus; Cancer Etiology; Capsid Proteins; Cell Communication; Cell Maturation; Cell Surface Receptors; Cell physiology; Cells; Cervical; Clinical Treatment; Clinical Trials; Co-Immunoprecipitations; Data; Development; Disease; Future; General Population; Genital system; Genotype; Goals; HIV; HIV Infections; HIV Seropositivity; HIV-1; HPV-High Risk; High Prevalence; Human; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Immune; Immune response; Immunity; Immunosuppression; Immunosuppressive Agents; In Vitro; Incidence; Individual; Infection; Infection prevention; Knowledge; L2 viral capsid protein; Langerhans cell; Lead; Lesion; Life Expectancy; Link; Liquid substance; Low risk HPV; Malignant Neoplasms; Malignant neoplasm of anus; Malignant neoplasm of cervix uteri; Mediating; Minor; Mucosal Immunity; Mucous Membrane; Natural Immunity; Oncogenic; Patients; Peptide Hydrolases; Phenotype; Play; Predisposition; Production; Publishing; Research; Risk; Role; Serine Proteinase Inhibitors; Site; Surface; T cell response; T-Lymphocyte; Testing; Therapeutic; Toll-like receptors; Viral; Viral Antigens; Woman; antileukoprotease; antimicrobial; cancer type; cellular targeting; cervical and anal cancer; combat; high risk; human SLPI protein; immunoregulation; knock-down; macrophage; men; novel; pathogen; prevent; public health relevance; receptor; respiratory; transmission process; uptake

DESCRIPTION (provided by applicant): Persistent high risk human papillomavirus (HPV) infection is a significant cause of anogenital cancers in HIV- positive individuals. The long-term goal of this study is to understand how HPV interacts with one of the same host receptors as HIV and to find new ways to treat HPV infection and associated diseases by activating innate immunity at mucosal surfaces. Secretory leukocyte protease inhibitor (SLPI) is a serine protease inhibitor found in mucosal fluids of the genital tract and has been shown to inhibit infection of macrophages by HIV by blocking the interaction of HIV with annexin A2 (ANXA2). One of the 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 and HIV infection. Our unpublished data suggest that the L2 capsid protein of HPV may mediate immune escape by interacting with ANXA2 on LC, thereby suppressing the maturation of LC. LC are also the initial cellular targets of HIV and play a critical role in viral dissemination. Therefore we will explore the relationship between HIV, HPV, ANXA2, and SLPI in LC in this proposal. Our published data show that it is possible to activate HPV-exposed LC with Toll-like receptor (TLR) agonists. However, it is unknown whether TLR agonists will be potent enough to overcome the suppressive effects of HPV-exposed LC from HPV and HIV co-infected individuals. 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) that treatment with TLR agonists will increase SLPI production and simultaneously induce HPV-exposed LC to activate HPV-specific T-cells from HPV/HIV co-infected patients. The following aims will be explored: Aim 1) Determine whether HPV16 L2 is responsible for suppressing the maturation of LC through interaction with ANXA2 and assess whether SLPI can block uptake of HPV and HIV by LC; Aim 2) Investigate whether TLR agonists up-regulate SLPI production by LC and induce HPV16- exposed LC to activate HPV16-specific T cells from patients infected with HPV or co-infected with HPV/HIV; and Aim 3) Determine whether apart from HPV16, other oncogenic HPV types also suppress LC maturation, and whether treatment of LC with TLR agonists reverses the immune escape of other high risk HPV genotypes that can cause cancer in HIV-infected individuals. These aims will be accomplished by performing co- immunoprecipitations and knock-down studies in LC to identify the HPV receptor. Reversal of immune suppression will be tested using immune-modulating compounds and immunosuppressive capacity of other HPV genotypes will be assessed by analyzing LC phenotype and function. This mechanistic research could lead to the identification of novel immune modulators with the goal of clearing persistent HPV infection in HIV- infected individuals and therefore reducing risk of developing more serious disease such as cervical, anal and other HPV-associated cancers. PUBLIC HEALTH RELEVANCE: Human papillomavirus (HPV) causes an increased incidence of several different types of cancer in HIV- infected individuals because of their immune suppression. With increased life expectancies due to advances in AIDS therapies and with high incidence of HPV co-infection, there is an urgent need to develop therapeutic strategies to reduce the risk and prevent the development of HPV-associated malignancies. Successful completion of this project will lead to a greater understanding of how HIV and HPV might co-interact with immune cells and the development of strategies to expedite HPV viral clearance in HIV-infected people by activating local innate immunity.

描述（由申请人提供）：持续高危人乳头瘤病毒（HPV）感染是 HIV 阳性个体患肛门生殖器癌症的重要原因。这项研究的长期目标是了解 HPV 如何与 HIV 相同的宿主受体之一相互作用，并通过激活粘膜表面的先天免疫来找到治疗 HPV 感染和相关疾病的新方法。分泌性白细胞蛋白酶抑制剂 (SLPI) 是一种在生殖道粘膜液中发现的丝氨酸蛋白酶抑制剂，已被证明可以通过阻断 HIV 与膜联蛋白 A2 (ANXA2) 的相互作用来抑制 HIV 巨噬细胞的感染。 HPV 逃避免疫的机制之一是在没有朗格汉斯细胞 (LC)（HPV 和 HIV 感染部位的抗原呈递细胞）共同刺激的情况下，通过抗原呈递诱导耐受。我们未发表的数据表明，HPV的L2衣壳蛋白可能通过与LC上的ANXA2相互作用来介导免疫逃逸，从而抑制LC的成熟。 LC 也是 HIV 的最初细胞靶标，在病毒传播中发挥着关键作用。因此，我们将在本提案中探讨 LC 中 HIV、HPV、ANXA2 和 SLPI 之间的关系。我们发表的数据表明，使用 Toll 样受体 (TLR) 激动剂可以激活 HPV 暴露的 LC。然而，尚不清楚 TLR 激动剂是否足以有效克服 HPV 和 HIV 共感染个体的 HPV 暴露 LC 的抑制作用。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 相互作用来抑制 LC 的成熟，2）TLR 激动剂治疗将增加 SLPI 的产生，同时诱导 HPV 暴露的 LC 激活来自 HPV/HIV 共感染患者的 HPV 特异性 T 细胞。将探讨以下目标： 目的 1) 确定 HPV16 L2 是否通过与 ANXA2 相互作用抑制 LC 的成熟，并评估 SLPI 是否可以阻止 LC 对 HPV 和 HIV 的摄取；目标 2) 研究 TLR 激动剂是否上调 LC 产生 SLPI，并诱导 HPV16 暴露的 LC 激活 HPV 感染或 HPV/HIV 合并感染患者的 HPV16 特异性 T 细胞；目标 3) 确定除了 HPV16 之外，其他致癌 HPV 类型是否也会抑制 LC 成熟，以及用 TLR 激动剂治疗 LC 是否可以逆转其他可能导致 HIV 感染者癌症的高风险 HPV 基因型的免疫逃逸。这些目标将通过在 LC 中进行免疫共沉淀和敲低研究来鉴定 HPV 受体来实现。将使用免疫调节化合物测试免疫抑制的逆转，并通过分析 LC 表型和功能来评估其他 HPV 基因型的免疫抑制能力。这项机制研究可能会导致新型免疫调节剂的鉴定，其目标是清除 HIV 感染者中持续的 HPV 感染，从而降低患上更严重疾病的风险，例如宫颈癌、肛门癌和其他 HPV 相关癌症。 公共卫生相关性：由于免疫抑制，人乳头瘤病毒 (HPV) 会导致 HIV 感染者几种不同类型癌症的发病率增加。由于艾滋病治疗的进步和 HPV 合并感染的高发生率导致预期寿命延长，迫切需要制定治疗策略来降低风险并预防 HPV 相关恶性肿瘤的发展。该项目的成功完成将有助于人们更好地了解 HIV 和 HPV 如何与免疫细胞相互作用，并制定通过激活局部先天免疫来加速 HIV 感染者体内 HPV 病毒清除的策略。