DAMPENING IMMUNODOMINANT EPITOPES

描述：(改编自申请者摘要)长期目标 本研究的目的是修饰和提高HIV-1的免疫原性 为了开发一种有效的HIV-1疫苗，我们开发了一种囊膜蛋白。 大多数人感染HIV-1会导致慢性、活动性 以及进行性感染，最终死于机会主义 感染和/或癌症。尽管引起了东道主的强烈反应 遗传不稳定病毒，慢性活动性感染正常 未经检查的收益。免疫反应最初针对的是有限的 病毒包膜上异常免疫显性的表位和 归根结底是非保护性的。“欺骗性的印记”，正如人们所知的， 似乎对免疫系统有诱骗和短路作用， 并倾向于阻止免疫系统引导其抗病毒 对更保守和功能更强的决定因素的活性参与 复制和/或发病机制。最近的研究旨在抑制或 屏蔽其中一个免疫优势表位V3，导致了 开发一种新的方法将免疫反应转移到更多 保守了分子的一部分。在这些研究中，一个以前沉默的， 二阶免疫反应系列，特点是程度更广 建立了中和的概念。额外的多变量和免疫力 除了V3结构域之外，还发现了阻滞性表位。这些 发生在gp20和gp41结构域中，是 这项提议。抑制这些遗传变量并增强感染 表位将允许其他更广泛的保护性表位触发 免疫反应。因此，广谱中和抗体和细胞介导的 可对从以下来源获得的初级HIV-1分离株产生反应 外周血单个核细胞(PBMC)和巨噬细胞类型。

DESCRIPTION: (Adapted from applicant's abstract) The long- term objective of this research is to modify and improve the immunogenicity of the HIV-1 envelope protein in order to develop an efficacious HIV-1 vaccine. Infection with HIV-1 in the majority of people results in a chronic, active and progressive infection ultimately ending in death from opportunistic infections and/or cancer. Although a vigorous host response is elicited to the genetically unstable virus, the chronic active infection normally proceeds unchecked. The immune response is initially directed at limited epitopes on the viral envelope that are unusually immunodominant and ultimately non-protective. "Deceptive Imprinting," as it has become known, appears to have a decoying and short-circuiting effect on the immune system, and tends to prevent the immune system from directing its anti-viral activity toward more conserved and functional determinants involved in replication and/or pathogenesis. Recent research aimed at dampening or masking one of these immunodominant epitopes, V3, resulted in the development of a novel approach to shift the immune response to more conserved parts of the molecule. In these studies, a previously silent, second order series of immune responses, characterized by a broader degree of neutralization, were established. Additional hypervariable and immune thwarting epitopes have been identified in addition to the V3 domain. These occur in both the gpl20 and gp41 domains and are the focus of research in this proposal. Dampening these genetically variable and infection-enhancing epitopes will allow other more broadly protective epitopes to trigger the immune response. Thus, broadly neutralizing antibody and cell-mediated responses may be generated against primary HIV-1 isolates obtained from peripheral blood mononuclear cells (PBMCs) and macrophage cell types.