HLA I DETERMINANTS OF CTL RESPONSE TO HIV INFECTION

HLA I 对 HIV 感染的 CTL 反应的决定因素

• 批准号: 6372669
• 负责人: FREDERICK S LEE
• 金额: $ 12.46万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6372669
• 关键词: HIV infections; MHC class I antigen; antigen presentation; cellular immunity; clinical research; cytokine; cytotoxic T lymphocyte; human immunodeficiency virus 1; human subject; pathologic process; protein biosynthesis; virus replication

Cytotoxic T lymphocytes (CTL) are hypothesized to play a critical role in the host immune response to HIV-1 infection. HIV-1 specific CTL kill virus-infected cells in a MHC-I restricted fashion and release cytokines/chemokines that inhibit viral replication. Our own data indicate these two modes of viral inhibition co-localize in the cytolytic granules of CTL. However, virus infection can lead to downregulation of MHC and consequent protection from CTL. Emerging data indicate that CTL are indeed associated with control of viremia in chronic HIV infection. Data from Ogg et al show that the magnitude of CTL, as determined by a novel flow-based assay which relies on staining of CTL with a tetrameric complex of HLA, beta 2 microglobulin and epitopic peptide, is negatively associated with viral load in untreated persons. However, these studies have only been performed in persons who are HLA A 0201-positive, and have only been performed for two peptide epitopes. Because numerous studies have now shown a link between certain HLA class I alleles and differences in disease progression, it is possible that this same correlation will not hold for all alleles. In addition, recent data from the Walker laboratory suggest that there are epitope-specific differences in the ability of CTL clones to effectively inhibit HIV replication. Furthermore, recent studies in a murine model of chronic viral infection indicate that CTL may exist in vivo that are incapable of carrying out effector function. These recent findings and preliminary data form the basis of a detailed project to assess the role of HLA class I alleles in the CTL response to HIV-1 infection. Specific aims include: (1) Use HLA class I-peptide tetramers to determine the correlation between CTL and viral load for alleles associated with relative protection (B27, B57), rapid progression (A24, B8), and intermediate progression (A2, A3, and B7); (2) Determine the ability of CTL clones to epitopes restricted by the above alleles to inhibit HIV-1 replication using cells transfected with these alleles as well as peripheral blood mononuclear cells (PBMC); (3) Determine the cytokine/chemokine profiles of CTL to defined epitopes and mechanisms of cell lysis.

细胞毒性T淋巴细胞(CTL)被认为在宿主对HIV-1感染的免疫反应中发挥关键作用。HIV-1特异性CTL以MHC-I限制性方式杀死病毒感染的细胞，并释放抑制病毒复制的细胞因子/趋化因子。我们自己的数据表明，这两种病毒抑制模式共同位于CTL的细胞溶解颗粒中。然而，病毒感染可导致MHC的下调，从而保护其免受CTL的侵害。新出现的数据表明，CTL确实与控制慢性HIV感染中的病毒血症有关。来自Ogg等人的数据显示，在未经治疗的人中，CTL的大小与病毒载量呈负相关，这是通过一种新的基于流动的分析方法确定的，该方法依赖于CTL与人类白细胞抗原、β2微球蛋白和表位多肽的四聚体复合体的染色。然而，这些研究只在HLAA0201阳性的人中进行，并且只针对两个肽表位进行。由于许多研究现已表明某些HLAI类等位基因与疾病进展的差异之间存在联系，因此这种相关性可能并不适用于所有等位基因。此外，来自沃克实验室的最新数据表明，CTL克隆有效抑制HIV复制的能力存在表位特异性差异。此外，最近在慢性病毒感染的小鼠模型中的研究表明，CTL可能存在于体内，而不能执行效应器功能。这些最新的发现和初步数据构成了一个详细项目的基础，该项目评估了人类白细胞抗原I类等位基因在HIV-1感染的CTL反应中的作用。具体目的包括：(1)使用HLAI类多肽四聚体来确定CTL与相对保护(B27，B57)、快速进展(A24，B8)和中间进展(A2，A3和B7)相关的等位基因的病毒载量之间的相关性；(2)确定CTL克隆对上述等位基因限制的表位的能力，通过使用这些等位基因的细胞以及外周血单核细胞(PBMC)来抑制HIV-1的复制；(3)确定CTL对所定义的表位和细胞溶解机制的细胞因子/趋化因子谱。