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: 6532619
• 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/6532619
• 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）被假设在宿主对HIV-1感染的免疫应答中起关键作用。 HIV-1特异性CTL以MHC-I限制的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，这两种模式的病毒抑制共定位在CTL的溶细胞颗粒。然而，病毒感染可导致MHC的下调和随后的CTL保护。 新出现的数据表明，CTL确实与控制慢性HIV感染的病毒血症有关。 Ogg等的数据表明，通过一种新的基于流动的测定法确定的CTL的大小与未治疗者的病毒载量呈负相关，该测定法依赖于用HLA、β 2微球蛋白和表位肽的四聚体复合物对CTL进行染色。 然而，这些研究仅在HLA A 0201阳性的人中进行，并且仅对两个肽表位进行。 由于许多研究已经表明某些HLA I类等位基因与疾病进展的差异之间存在联系，因此可能并非所有等位基因都存在相同的相关性。 此外，最近来自步行者实验室的数据表明，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鼠模型中的研究表明，CTL可能存在于体内，其不能执行效应子功能。 这些最新的发现和初步数据的基础上，一个详细的项目，以评估HLA I类等位基因的作用，在CTL应答HIV-1感染。 具体目标包括：（1）使用HLA I类肽四聚体来确定CTL与相对保护相关等位基因的病毒载量之间的相关性（B27，B57）、快速进展（A24，B8）和中度进展（A2、A3和B7）;（2）确定针对上述等位基因限制的表位的CTL克隆抑制HIV-1的能力。1复制使用这些等位基因转染的细胞以及外周血单核细胞（PBMC）;（3）确定CTL对确定的表位的细胞因子/趋化因子谱和细胞裂解机制。