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: 7854118
• 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/7854118
• 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; 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; Pan Genus; Patients; Peptide Hydrolases; Phenotype; Play; Predisposition; Production; Publishing; Research; Risk; Role; Serine Proteinase Inhibitors; Site; Surface; 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; response; 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）：持续性高危人乳头瘤病毒（HPV）感染是HIV阳性个体发生肛门生殖器癌的重要原因。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寻找治疗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，并已显示通过阻断HIV与膜联蛋白A2（ANXA 2）的相互作用来抑制HIV对巨噬细胞的感染。HPV逃避免疫的机制之一是在不存在朗格汉斯细胞（LC）（HPV和HIV感染部位的抗原呈递细胞）共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ANXA 2相互作用介导免疫逃逸，从而抑制LC的成熟。LC也是HIV的初始细胞靶点，在病毒传播中起关键作用。因此，我们将探讨HIV，HPV，ANXA 2和SLPI在LC中的关系。我们发表的数据表明，它是可能的激活HPV暴露的LC与Toll样受体（TLR）激动剂。然而，TLR激动剂是否足够有效以克服来自HPV和HIV共感染个体的HPV暴露的LC的抑制作用尚不清楚。我们假设：1）为了逃避T细胞免疫，HPV 16 L2通过与细胞表面受体ANXA 2相互作用抑制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HPV/HIV共感染患者的HPV特异性T细胞。目的1）确定HPV 16 L2是否通过与ANXA 2相互作用来抑制LC的成熟，并评估SLPI是否可以阻断LC对HPV和HIV的摄取;目的2）研究TLR激动剂是否通过LC上调SLPI的产生并诱导HPV 16暴露的LC激活来自HPV感染或与HPV共感染的患者的HPV 16特异性T细胞。艾滋病毒;和目的3）确定除了HPV 16之外，其它致癌HPV类型是否也抑制LC成熟，以及用TLR激动剂治疗LC是否逆转可在HIV感染个体中引起癌症的其它高风险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以鉴定HPV受体来实现。将使用免疫调节化合物检测免疫抑制的恢复，并通过分析LC表型和功能评估其他HPV基因型的免疫抑制能力。这种机制研究可能导致识别新的免疫调节剂，其目标是清除HIV感染个体中的持续HPV感染，从而降低发展更严重疾病的风险，如宫颈癌、肛门癌和其他HPV相关癌症。 公共卫生相关性：人乳头瘤病毒（HPV）由于其免疫抑制而导致HIV感染个体中几种不同类型癌症的发病率增加。随着艾滋病治疗的进步和HPV合并感染的高发病率导致的预期寿命增加，迫切需要开发治疗策略以降低HPV相关恶性肿瘤的风险并预防其发展。该项目的成功完成将使人们更好地了解艾滋病毒和HPV如何与免疫细胞相互作用，并制定策略，通过激活局部先天免疫来加快艾滋病毒感染者的HPV病毒清除。