PROTEIN SORTING TO ENHANCE IMMUNE RESPONSES TO HIV

蛋白质分选可增强对 HIV 的免疫反应

• 批准号: 2887893
• 负责人: M ABDUL JABBAR
• 金额: $ 24.68万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2001-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2887893
• 关键词: AIDS vaccines; HIV envelope protein gp120; HIV envelope protein gp160; Macaca mulatta; cellular immunity; chimeric proteins; cytotoxic T lymphocyte; enzyme linked immunosorbent assay; fusion gene; helper T lymphocyte; human immunodeficiency virus 1; humoral immunity; laboratory mouse; vaccine development; vector vaccine; virus antigen

DESCRIPTION (Adapted from applicant's abstract): Primary HIV infection appears to be effectively controlled by both CTL and antibody responses. The kinetics and peak level of CTL response correlates with a reduction in the levels of viremia in HIV-infected individuals. This protective role of CTL is not sustained during progression to AIDS. Immune escape has been proposed to be one of the mechanisms for the failure of anti-HIV CTL. In the early CTL population, there is a preponderance of responses to Envelope, Gag (structural) and Nef (regulatory) proteins of HIV-1. Gag and Nef are made in the cytosol before delivery to the plasma membrane by post-translational modification by N-myristoylation. It is therefore conceivable that Gag and Nef are exposed to the cytosolic ubiquitin-proteosome pathway, which generates epitopes for presentation by HLA class I antigens. However, the generation of env-specific CTL is hard to conceptualize as the envelope glycoprotein is translocated into the ER, the compartment where antigenic peptide epitopes assemble with class I molecules. This mode of Env biosynthesis in the secretory pathway is not optimal for efficient generation and presentation of peptides to HLA class I. However, HIV infected individuals do generate CTL that are envelope specific indicating that HIV Env is accessible to the antigen presentation pathway during its biosynthesis. It is likely that the exposure of Env to the proteosome is only limited and thereby would generate only a limited set of CTL epitopes. The applicant hypothesize that specific ER degradation of HIV Env has the potential to generate antigenic peptides more efficiently in the cell and thereby expand the repertoire of antigen selection and presentation. To achieve a sequence-specific selective degradation of HIV envelope glycoproteins in the ER, the applicant will use the HIV-1 Vpu protein. Previous in vitro studies have shown that HIV-1 Vpu induces the ER degradation of HIV-1 envelope glycoproteins appended to CD4 trans-membrane and cytoplasmic domains. We hypothesize that this property of the HIV Vpu protein could enhance the generation of Env peptides for presentation by MHC class I antigens in vivo. Since Env-CD4 proteins are anchored to the cell membrane, they would also retain the ability to induce antibody responses with or without Vpu. The applicant will test this notion by introducing in animals (mice and monkeys) the genes encoding EnvCD4 and Env-Gag-CD4 fusion proteins as DNA vaccines in the presence and absence of the Vpu expression plasmid. The applicant will perform initial experiments in mice to test the proof of principle that specific ER degradation of Env would enhance env-specific CTL and antibody responses. Prospective vaccine constructs will be used to immunize rhesus macaques and immune protection will be assessed by challenging vaccinated monkeys with pathogenic SHIV isolates. This line of inquiry has the potential to reveal the modality of antigen presentation for the design of an effective AIDS vaccine.

描述（改编自申请人的摘要）：原发性艾滋病毒感染 似乎由CTL和抗体反应有效控制。 CTL响应的动力学和峰值水平与降低相关 艾滋病毒感染者的病毒血症水平。 这种保护作用 CTL在艾滋病的发展过程中无法持续。 免疫逃生已经 被认为是抗HIV CTL失败的机制之一。 在 早期的CTL种群，对信封的反应很大， HIV-1的GAG（结构）和NEF（调节）蛋白。 堵嘴和nef是 在传递到质膜之前，用细胞质制成 通过n- myristoylation进行翻译后修饰。 因此是 可以想象，插科打nef暴露于胞质 泛素 - 蛋白酶体途径，该途径生成以示例性的表位 HLA I类抗原。 但是，ENV特异性CTL的产生很难 概念化为信封糖蛋白被转移到ER中， 抗原肽表位与I类组装的隔室 分子。 这种分泌途径中的Env Biosynsiss的这种模式不是 最佳的有效产生和肽呈现给HLA类 I.但是，艾滋病毒感染的个体确实会产生信封的CTL 具体表明抗原表现可以使用HIV Env 其生物合成期间的途径。 env可能会暴露于 蛋白体仅受到限制，因此只会产生有限的集合 CTL表位。 申请人假设特定的ER降解 HIV Env有可能在更有效地产生抗原肽 细胞，从而扩大抗原选择的曲目和 推介会。 实现艾滋病毒的序列特异性选择性降解 ER中的信封糖蛋白，申请人将使用HIV-1 VPU 蛋白质。 以前的体外研究表明，HIV-1 VPU诱导ER HIV-1信封糖蛋白的降解附加到CD4跨膜 和细胞质结构域。 我们假设HIV VPU的这一特性 蛋白质可以增强ENV肽的产生，以通过MHC呈现 体内I类抗原。 由于Env-CD4蛋白固定在细胞上 膜，它们还将保留诱导抗体反应的能力 有或没有VPU。申请人将通过引入 动物（小鼠和猴子）编码envcd4和env-gag-cd4融合的基因 在存在和不存在VPU表达的情况下，蛋白作为DNA疫苗 质粒。 申请人将在小鼠中进行初始实验，以测试 原则证明ENV的特定ER退化将增强 ENV特异性CTL和抗体反应。 前瞻性疫苗结构 将用于免疫猕猴，免疫保护将是 通过挑战致病性湿腹株的疫苗接种猴子进行评估。 这种调查线有可能揭示抗原的方式 用于设计有效艾滋病疫苗的演示文稿。

项目成果

A single red InGaN-based light-emitting diode with a europium (III) ternary complex as mono-phosphor.

• DOI: 10.1016/j.saa.2007.06.015
• 发表时间: 2008-04
• 期刊: Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy
• 作者: Nengjun Xiang;Yong Xu;Zhengliang Wang;Xiao-xiao Wang;L. Leung;Jing Wang;Q. Su;M. Gong