HIV ENVELOPE PEPTIDE-BASED VACCINE IN SHIV-RHESUS MODEL

描述（改编自申请人摘要）：免疫学 保护免受人类免疫缺陷病毒1型的相关因素 艾滋病病毒（HIV-1）感染与获得性免疫缺陷综合征的发展 （艾滋病）还不清楚。申请人假设， 有效预防艾滋病毒引起艾滋病的疫苗接种战略应包括 细胞介导免疫（CMI）的优先诱导。这一假设 最近的报道支持了辅助性T细胞的存在 针对某些HIV肽的应答，和/或HIV特异性 细胞毒性T淋巴细胞（CTL）反应，而不是抗体，在长期 非进展者，以及某些尽管 沉迷于高风险活动。该应用程序的长期目标是 以合成肽为基础的疫苗， CMI，因为它提供了定义，安全和经济的优势。 在这方面，保护免受某些疾病和死亡的影响， 在使用基于肽的疫苗的动物模型中证实了病毒， 有效启动CMI反应。使用一系列动物模型 （鼠类、恒河猴和黑猩猩），以及来自HIV感染的 人，调查人员先前已经确定了几个艾滋病毒的env 来自高度保守区域的肽，其诱导HIV特异性T细胞 在没有抗体反应的情况下。最近，他们 分析了来自HIV血清阳性长期非进展者的PBMC，并观察到 针对相同保守HIV-1的HLA C类限制性CD 8 + CTL应答 env肽。HIV包膜蛋白在HIV感染中起着重要作用。 病毒诱导的发病机制，并已成为疫苗策略的重点。 然而，由于缺乏合适的HIV诱导的艾滋病动物模型， 这些努力最近开发的嵌合病毒SHIV，由HIV 包膜和SIV核心，在猕猴中诱导艾滋病样疾病，因此 为检测HIV env疫苗提供了最佳替代方案， 治疗学研究人员假设，保守的HIV包膜蛋白 他们鉴定的肽可以作为疫苗， 恒河猴中的CMI和对致病性SHIV攻击的保护。到 为了测试他们的疫苗策略，他们提出了两种具体的方法， 恒河猴的免疫：（i）用弗氏（Freund's）中的肽混合物 佐剂，和（ii）用自体树突细胞（DC），预处理， 体外与肽混合物。在用致病性SHIV攻击后， 申请人期望两个实验中的动物都将发育 有效的病毒特异性CMI应答，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.