HIV ENVELOPE PEPTIDE-BASED VACCINE IN SHIV-RHESUS MODEL

描述(改编自申请人的摘要)：免疫学 预防人类免疫缺陷病毒1型的相关因素 艾滋病病毒(HIV-1)感染与艾滋病的发生发展 (艾滋病)并不是很清楚。申请者假设一个 针对艾滋病毒引起的艾滋病的有效疫苗接种战略应包括 优先诱导细胞免疫(CMI)。这一假设已经 最近关于辅助性T细胞存在的报道支持这一观点 针对某些HIV多肽和/或HIV特异性的反应 长期的细胞毒性T淋巴细胞(CTL)反应，而不是抗体 无进展者，以及某些艾滋病毒阴性的人，尽管 沉迷于高风险的活动。该应用程序的长期目标是 研制一种合成多肽疫苗，用于启动HIV特异性 CMI，因为它提供了定义、安全和经济的优势。 在这方面，对某些疾病和死亡的保护 病毒在使用基于多肽的疫苗的动物模型中得到证实 有效启动CMI响应。使用一系列动物模型 (小鼠、恒河猴和黑猩猩)，以及感染艾滋病毒的样本 此前，调查人员已经确认了几个HIV病毒的包围者 来自高度保守区域的多肽，可以诱导HIV特异性T细胞 在没有抗体反应的情况下产生反应。最近，他们已经 分析HIV血清阳性长期无进展者的PBMC并观察 人类白细胞抗原C类限制性CD8+CTL对相同保守HIV-1的免疫应答 环境多肽。HIV包膜蛋白在 病毒诱导的致病机制和疫苗策略一直是研究的重点。 然而，缺乏合适的艾滋病毒引起的艾滋病的动物模型阻碍了 这些努力。最近开发的嵌合病毒Shiv，由HIV组成 包膜和SIV核心，在猕猴中诱导类似艾滋病的疾病，因此 为测试基于HIV env的疫苗提供最佳替代方案 治疗学。研究人员推测，保守的HIV病毒包膜 他们确定的多肽，可以作为疫苗来诱导有效的 恒河猴CMI及其对致病性SHV攻击的保护作用。至 测试他们的疫苗策略，他们提出了两种具体的方法，包括 恒河猴免疫：(I)弗氏多肽混合物 佐剂，和(Ii)自体树突状细胞(DC)，在 与多肽混合物进行体外实验。在挑战致病的希沃克病毒时， 申请者希望这两个实验中的动物都能发育。 高效的病毒特异性CMI反应，并抵抗感染和/或疾病。

DESCRIPTION (adapted from applicant's abstract): The immunological correlates for protection against human immunodeficiency virus type 1 (HIV-1) infection and development of acquired immunodeficiency syndrome (AIDS) are not clearly understood. The applicants have hypothesized that an effective vaccination strategy against HIV-induced AIDS should involve preferential induction of cell-mediated immunity (CMI). This hypothesis has been supported by recent reports describing presence of helper T-cell responses directed against certain HIV peptides, and/or HIV-specific cytotoxic T lymphocyte (CTL) responses, but not antibodies, in long-term nonprogressors, and in certain individuals who remain HIV-negative despite indulging in high-risk activities. The long-term goal of the application is to formulate a synthetic peptide-based vaccine, for priming HIV-specific CMI, because it offers the advantage of being defined, safe, and economical. In this regard, protection against disease and death induced by certain viruses was demonstrated in animal models using peptide-based vaccines for efficient priming of CMI responses. Using a series of animal models (murine, and rhesus and chimpanzee monkeys), and samples from HIV-infected people, the investigators have previously identified several HIV env peptides, from highly conserved regions, that induce HIV-specific T-cell response in the absence of antibody response. More recently, they have analyzed PBMCs from HIV-seropositive long-term nonprogressors and observed HLA class C-restricted CD8+ CTL responses against the same conserved HIV-1 env peptides. The HIV envelope protein plays a major role in the virus-induced pathogenesis and has been the focus of vaccine strategies. However, the lack of a suitable animal model for HIV-induced AIDS hampered these efforts. The recently developed chimeric virus SHIV, comprised of HIV envelope and SIV core, induces AIDS-like disease in macaques, and thus provides the best alternative for testing HIV env-based vaccines and therapeutics. The investigators hypothesize that the conserved HIV env peptides they identified, can function as a vaccine for inducing efficient CMI and protection against pathogenic SHIV challenge in rhesus monkeys. To test their vaccine strategy, they propose two specific approaches involving immunization of rhesus monkeys: (i) with the peptide-mixture in Freund's adjuvant, and (ii) with autologous dendritic cells (DCs), pretreated in vitro with the peptide-mixture. Upon challenge with the pathogenic SHIV, the applicants expect that animals in both experiments will develop efficient virus-specific CMI responses, and resist infection and/or disease.