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

• 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
• 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

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，在美国，有110万人患有人类免疫缺陷病毒（HIV），每年有超过56,000个新感染。在这些新感染中，有12％是静脉吸毒的直接结果（IDU，污染针共享），而32％是由于IDU相关的行为（异性恋和同性恋与IDU个人的接触）。根据疾病控制中心的说法，IDU被认为是艾滋病毒感染的第三大重要危险因素，这些风险群体超过了与从事非保护异性恋接触的男人和个人发生性关系的危险群体。虽然预防药物使用和治疗可以减轻艾滋病毒的发病率，但由于鉴于IDU个人的数量和社会经济地位，目前可能无法实现这一点，因此目前可能无法实现。因此，与此同时，该疾病的治疗是关键。对于美国和患有艾滋病毒的发展中国家的人来说，高度活跃的抗逆转录病毒疗法（HAART）已成为治疗的中流。 HAART的新事态发展导致了不可检测的病毒血症，CD4+ T细胞计数，更好的生活质量以及总体改善生存的患者数量的增加。然而，许多问题通过出现逃生突变体的出现，患者的不可接受和不遵守，不良副作用以及对持续治疗的需求仍然存在。重要的是，Haart不会影响继续产生病毒的细胞。结果，大多数HAART患者患有低水平的病毒血症，必须无限期保留治疗以防止病毒反弹。为了解决这个问题，我们建议使用针对HIV GP160的第一代和辅助腺病毒载体，该载体和辅助腺病毒载体编码广泛中和抗体（BNAB）。这样的BNAB可以靶向表达抗原的，感染的细胞，以通过宿主免疫系统消除，并且使用腺病毒载体可为长期转基因表达的各种细胞类型提供高效率转导。首先，特征良好的BNAB将在第一代和辅助腺病毒系统的背景下进行编码。其次，我们将生产并净化载体颗粒的高点库存，以进行体外表征。第三，通过使用人源化的HIV感染小鼠模型来确定BNAB在减少病毒复制方面的有效性，将在体内测试VECTR颗粒。在此提案中，将与纯化的重组BNAB和第一代腺病毒并行测试，与辅助腺病毒相比，将与纯化的重组BNAB并行测试。将测试编码BNAB的各种组合，以确定靶向不同表位是否提高了功效。这些目标的完成应洞悉腺病毒介导的载体递送和宿主中和抗HIV抗体反应，并为新的矢量介导的长期持续疗法提供潜力，最终可能会降低受感染者（包括使用药物的人）所需的频率和持续时间。