Using adenoviral vectors to express broadly neutralizing anti-gp160 antibodies

使用腺病毒载体表达广泛中和的抗 gp160 抗体

基本信息

批准号：
8463808
负责人：
Shan Liu
金额：
$ 4.22万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-16 至 2014-04-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8463808
关键词：
Address Adenovirus Vector Adenoviruses Adherence Adverse effects Affect African Alcohol or Other Drugs use Animal Model Animals Anti-Retroviral Agents Antibodies Antibody Formation Antigen Targeting Behavior Biological Assay Biological Models CD4 Positive T Lymphocytes Cell Count Cells Centers for Disease Control and Prevention (U.S.)Characteristics Clinical Code Coitus Controlled Clinical Trials Couples Development Disease Dose Effectiveness Epitopes Escape Mutant Failure Frequencies Funding Generations Goals HIV Half-Life Hepatocyte Heterosexuals Highly Active Antiretroviral Therapy Homosexuals Immune Immune system Immunocompetent In Vitro Incidence Individual Infection Life Mediating Needles Oral Patients Pharmaceutical Preparations Plasma Prophylactic treatment Proteins Quality of life Recombinant Proteins Recombinants Regimen Research Resources Risk Risk Factors Safety Socioeconomic Status Source System Tenofovir Testing Therapeutic Therapeutic Effect Time United States Vagina Viral Viral Load result Viremia Virus Virus Diseases Woman adenoviral-mediated base cell type drug abuse prevention drug resistant virus effective therapy experience gp160 helper-dependent adenoviral vector immunogenic improved in vivo insight intravenous drug use killings man memory CD4 T lymphocyte men who have sex with men mouse model neutralizing antibody novel particle prevent restoration success transduction efficiency transgene expression transmission process truvada vector

项目摘要

DESCRIPTION (provided by applicant): Recent estimates have suggested there are 1.1 million individuals living with human immunodeficiency virus (HIV) in the United States with over 56,000 new infections arising annually. Of these new infections, 12% are a direct result of intravenous drug use (IDU, sharing of contaminated needles) and 32% are due to IDU-associated behaviors (heterosexual and homosexual contact with an IDU individual). According to the Centers for Disease Control, IDU is considered the third most important risk factor for HIV infection, surpassed by the risk groups of men who have sex with men and individuals engaging in unprotected heterosexual contact. While drug use prevention and treatment can alleviate the incidence of HIV, this may not be currently achievable due to inadequate funding and access to resources given the number and socioeconomic status of IDU individuals; thus in the meantime treatment of the disease is key. For individuals in the US and developing world who live with HIV, highly active antiretroviral therapy (HAART) has become the mainstay of treatment. New developments in HAART have given rise to increasing numbers of patients with undetectable viremia, higher CD4+ T-cell counts, better quality of life, and overall improved survival. However, many issues remain by way of emergence of escape mutants, patient inaccessibility and non-adherence, adverse side effects and the need for ongoing treatment. Importantly, HAART does not affect cells that continue to produce virus. As a result, most patients on HAART have low-level viremia and must remain on treatment indefinitely to prevent viral rebound. To therapeutically address this issue, we propose the use of first generation and helper-dependent adenoviral vectors encoding broadly neutralizing antibodies (bnAbs) against HIV gp160. Such bnAbs can target antigen-expressing, infected cells for elimination by the host immune system, and the use of adenoviral vectors gives high efficiency transduction of diverse cell types for long-term transgene expression. First, well-characterized bnAbs will be encoded in the context of first generation and helper-dependent adenoviral systems. Second, we will produce and purify high-titer stocks of vector particles for in vitro characterization. Third, vectr particles will be tested in vivo with the use of a humanized mouse model of HIV infection to determine the effectiveness of the bnAbs in reducing viral replication. In this proposal vector-encoded bnAbs will be tested in parallel against purified recombinant bnAbs, and first generation adenoviruses compared with helper-dependent adenoviruses. Various combinations of encoded bnAbs will be tested to determine if targeting different epitopes improves efficacy. The completion of these objectives should provide insight into adenoviral-mediated vector delivery and host-neutralizing anti-HIV antibody responses, as well as offer the potential for new vector-mediated means of long-lasting therapy that may eventually reduce the frequency and duration of HAART required for infected individuals, including those who use substances.

描述（由申请人提供）：最近的估计表明，美国有 110 万人感染人类免疫缺陷病毒 (HIV)，每年新增感染病例超过 56,000 例。在这些新感染中，12% 是静脉吸毒（IDU，共用受污染针头）的直接结果，32% 是由于 IDU 相关行为（与 IDU 个体的异性和同性恋接触）造成的。根据疾病控制中心的数据，注射吸毒者被认为是艾滋病毒感染的第三大危险因素，仅次于男男性行为者和进行无保护异性接触的个人的危险人群。虽然吸毒预防和治疗可以降低艾滋病毒的发病率，但考虑到吸毒者的数量和社会经济地位，由于资金和资源获取不足，目前这可能无法实现；因此，与此同时，治疗该疾病是关键。对于美国和发展中国家的艾滋病毒感染者来说，高效抗逆转录病毒疗法（HAART）已成为主要的治疗方法。 HAART 的新进展使越来越多的患者出现无法检测到的病毒血症、CD4+ T 细胞计数增加、生活质量提高以及总体生存率提高。然而，由于逃逸突变体的出现、患者难以接近和不依从、不良副作用以及持续治疗的需要，许多问题仍然存在。重要的是，HAART 不会影响继续产生病毒的细胞。因此，大多数接受 HAART 的患者都患有低水平病毒血症，必须无限期地继续治疗以防止病毒反弹。为了在治疗上解决这个问题，我们建议使用第一代辅助依赖性腺病毒载体，编码针对 HIV gp160 的广泛中和抗体 (bnAb)。这种bnAb可以靶向表达抗原的感染细胞，以便被宿主免疫系统消除，并且腺病毒载体的使用可以高效转导不同细胞类型以实现长期转基因表达。首先，特征良好的 bnAb 将在第一代和辅助依赖性腺病毒系统的背景下进行编码。其次，我们将生产和纯化用于体外表征的高滴度载体颗粒库存。第三，将使用 HIV 感染的人源化小鼠模型对 vectr 颗粒进行体内测试，以确定 bnAb 在减少病毒复制方面的有效性。在该提案中，载体编码的 bnAb 将与纯化的重组 bnAb 进行平行测试，并将第一代腺病毒与辅助依赖性腺病毒进行比较。将测试编码的 bnAb 的各种组合，以确定针对不同表位是否可以提高功效。这些目标的完成应有助于深入了解腺病毒介导的载体传递和宿主中和抗 HIV 抗体反应，并提供新的载体介导的长期治疗方法的潜力，最终可能减少治疗的频率和持续时间。感染者（包括使用药物的人）需要进行高效抗逆转录病毒疗法（HAART）。