INHIBITION OF HIV-1 REPLICATION BY CYTOTOXIC LYMPHOCYTES

尽管HIV-1被鉴定为艾滋病的病原体， 获得性免疫缺陷综合征（艾滋病）的定义， 针对该病毒的免疫应答仍然是一个难以实现的目标。 一 已经检测到对HIV-1的强烈细胞毒性淋巴细胞（CTL）应答 体外数据表明，淋巴细胞 来自CD 8表型的感染个体的抗体可以抑制病毒 体外复制。 功能研究表明，这些细胞是 典型的CTL，但尚未识别相关的靶抗原。 鉴定 我们的实验室最近建立了一种技术， HIV-1特异性CTL克隆的分离和长期增殖，以及 已经绘制了这些细胞识别的实际CTL表位， 合成病毒肽。 本提案的目的是审查 确定表位特异性的CTL克隆抑制肿瘤细胞增殖的能力， HIV-1复制，以确定 这些细胞在体外。 具体而言，我们建议（1）检查 CTL克隆抑制HIV-1在淋巴细胞中复制的能力（2） 检测CTL克隆抑制HIV-1复制的能力， 单核细胞（3）确定CTL诱导的抑制机制， 病毒复制（4）决定抗原变异在 逃避CTL的识别。 这些研究都应该提供洞察力 HIV-1感染的免疫发病机制，并直接 与潜在的HIV-1免疫和免疫治疗策略相关。

Despite the identification of HIV-1 as the causative agent of the acquired immune deficiency syndrome (AIDS), definition of a protective immune response against the virus has remained an elusive goal. A vigorous cytotoxic lymphocyte (CTL) response to HIV-1 has been detected in infected individuals, and in vitro data indicate that lymphocytes from infected individuals of the CD8 phenotype can inhibit virus replication in vitro. Functional studies suggest that these cells are typical CTL, yet the relevant target antigens recognized have not been identified. Our laboratory has recently established a technique for the isolation and long-term propogation of HIV-1-specific CTL clones, and have mapped the actual CTL epitopes recognized by these cells using synthetic viral peptides. The purpose of this proposal is to examine the ability of CTL clones of defined epitope specificity to inhibit the replication of HIV-1 in order to determine the functional activity of these cells in vitro. Specifically, we propose to (1) examaine the ability of CTL clones to inhibit replication of HIV-1 in lymphocytes (2) examine the ability of CTL clones to inhibit HIV-1 replication in monocytes (3) determine the mechanisms of the CTL-induced inhibition of virus replication (4) determine the role of antigenic variation in escape from CTL recognition. These studies should both provide insight into the immunopathogenesis of HIV-1 infection, and are directly relevant to potential HIV-1 immunization and immunotherapy strategies.