Optimizing CD8+ T-cell responses against C clade HIV infection in subSaharan Afri

优化 CD8 T 细胞对撒哈拉以南非洲 C 分支 HIV 感染的反应

基本信息

批准号：
8282630
负责人：
PHILIP J GOULDER
金额：
$ 47.03万
依托单位：
UNIVERSITY OF OXFORD
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-15 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8282630
关键词：
AIDS Vaccines Accounting Address Affect Africa South of the Sahara African Alleles Animal Model Antigens Antiviral Agents Biological Assay CD8B1 gene Cells Cessation of life Clinic Data Data Set Databases Development Disease Progression Epidemic Epitopes Escape Mutant Future Gagging Gel Goals Grant HIV HIV Infections HIV Vaccine Trials Network HIV vaccine HLA-B Antigens HLA-C Antigens Human Immune Immune response Individual Infection Infection prevention Knowledge Mothers Peptide/MHC Complex Peptides Play Population Proteins Role Sampling South Africa Southern Africa Speed Study Subject T cell response T-Lymphocyte T-Lymphocyte Epitopes Testing Time Vaccinated Vaccination Vaccine Design Vaccines Viral Virus Work antiretroviral therapy base combat cost gag-pol Fusion Proteins immunogenic improved microbicide novel novel strategies pressure prevent response transmission process

项目摘要

DESCRIPTION (provided by applicant): CD8+ T-cell T-cells can be a central role in immune control of HIV infection. However, the CD8+ T-cell responses that should be induced by an HIV vaccine in order to be optimally effective are yet to be established. Work we have done in the course of the previous 5 years of this grant have focused on the southern African HIV epidemic, the region worst affected by HIV and most urgently in need of an effective vaccine. One major conclusion that can be drawn from the work we have done in the past 5 years of this grant is that immune control of HIV infection is facilitated by a broad Gag-specific CD8+ T-cell response, in particular by responses in Gag, but also to a lesser extent in Pol, that can drive selection pressure on the virus. It is apparent that some of the most efficacious responses are subdominant to other, ineffective responses. Epitope efficacy differs between proteins (Gag>Pol>Acc-Reg>Env), but also within proteins. Epitope efficacy also differs acording to HLA restriction. HLA-B-restricted responses have the greatest impact on viral setpoint, and drive the strongest selection pressure on the virus. HLA-C-restricted responses are associated with high viral setpoint even when they are Gag-specific. The goal of the first specific aim of these proposed studies is, using a novel approach to achieve rapid definition of CTL epitopes, to identify those responses, including subdominant responses, in Gag and Pol that are most effective in inhibition of HIV replication. It is quite clear that current knowledge of the optimal epitopes targeted, and the CD8+ T-cell response hierarchy even for the most prevalent HLA alleles, remains inadequate in order to understand the CD8+ T-cell response in natural HIV infection and what perturbations of this response hierarchy may be needed to optimise the CD8+ T-cell contribution to immune control of HIV. For an allele such as A*6802, present in 1/6 of the southern African population, currently described optimal epitopes account for only 1% of the actual responses made by A*6802-positive subjects that are restricted by that alelle. The novel approach, involved use of peptide-MHC tetramers, is rapid and inexpensive, has been validated by us as shown in preliminary data presented, and crucially provides the further opportunity to assess the efficacy of purified antigenic-specific cells in viral inhibition assays. The second aim of these studies is to investigate the ability of a T-cell vaccine in humans to alter the response hierarchy observed in natural infection. We will study the South African subjects who were vaccinated with the MRK Ad5 vaccine (HVTN 503, 'Phambili' study), which expressed Gag, Pol and Nef. Using our database of 1,015 south African study subjects in whom we have characterized the CD8+ T-cell responses against C clade infection, using a panel of 410 overlapping 18mer peptides, we will be able to determine whether this MRK Ad5 T-cell vaccine, which has already been shown to boost specifically Gag, Pol and Nef responses in post-infection vaccinees, can alter the response hierarchy that is seen in non-vaccinated infected people. This would be an important prerequisite for a T-cell vaccine to be effective. The final specific aim of these proposed studies is to investigate the impact of viral adaptation to the CD8+ T-cell response hierarchy. We have shown in the previous 5 years' work that viral adaptation is occurring at a population level, such that escape mutants in even the most protective epitopes are accumulating over time. How fast, and the extent to which, these escape mutants accumulate will be considered in these proposed studioes, to determine whether viral adaptation in fact is likely to have an impact on current T-cell vaccine design.

描述（由申请人提供）：CD8+ T 细胞 T 细胞在 HIV 感染的免疫控制中发挥着核心作用。然而，HIV 疫苗应诱导 CD8+ T 细胞反应才能发挥最佳效果，这一点尚未确定。我们在这笔赠款的前 5 年中所做的工作主要集中在南部非洲的艾滋病毒流行上，该地区是受艾滋病毒影响最严重、最迫切需要有效疫苗的地区。从我们在过去 5 年的这项资助中所做的工作中可以得出的一个主要结论是，广泛的 Gag 特异性 CD8+ T 细胞反应，特别是 Gag 中的反应，促进了 HIV 感染的免疫控制，但是在波尔，这也可以在较小程度上增加对病毒的选择压力。很明显，一些最有效的反应是次于其他无效反应的。表位功效在蛋白质之间存在差异（Gag>Pol>Acc-Reg>Env），而且在蛋白质内部也存在差异。表位功效也因 HLA 限制而异。 HLA-B 限制性反应对病毒设定点影响最大，并对病毒产生最强的选择压力。 HLA-C 限制反应与高病毒设定点相关，即使它们是 Gag 特异性的。这些拟议研究的第一个具体目标是，使用一种新方法来实现 CTL 表位的快速定义，以确定 Gag 和 Pol 中最有效抑制 HIV 复制的反应，包括次显性反应。很明显，目前对最佳目标表位的了解，以及即使对于最常见的 HLA 等位基因的 CD8+ T 细胞反应层次结构，仍然不足以了解自然 HIV 感染中的 CD8+ T 细胞反应以及这种反应的扰动。可能需要反应层次来优化 CD8+ T 细胞对 HIV 免疫控制的贡献。对于存在于南部非洲人口 1/6 的 A*6802 等等位基因，目前描述的最佳表位仅占受该等位基因限制的 A*6802 阳性受试者实际反应的 1%。这种涉及使用肽-MHC 四聚体的新方法快速且廉价，已得到我们的验证，如初步数据所示，并且至关重要的是，提供了进一步评估纯化的抗原特异性细胞在病毒抑制测定中的功效的机会。这些研究的第二个目的是调查人类 T 细胞疫苗改变自然感染中观察到的反应等级的能力。我们将研究接种 MRK Ad5 疫苗的南非受试者（HVTN 503，“Phambili”研究），该疫苗表达 Gag、Pol 和 Nef。利用我们包含 1,015 名南非研究对象的数据库，我们在其中描述了针对 C 分支感染的 CD8+ T 细胞反应，并使用一组 410 个重叠的 18mer 肽，我们将能够确定这种 MRK Ad5 T 细胞疫苗是否已被证明可以特别增强感染后疫苗接种者的 Gag、Pol 和 Nef 反应，可以改变未接种疫苗的感染者的反应等级。这将是 T 细胞疫苗有效的重要先决条件。这些拟议研究的最终具体目标是调查病毒适应对 CD8+ T 细胞反应层次的影响。我们在过去五年的工作中表明，病毒适应正在群体水平上发生，因此即使是最具保护性的表位中的逃逸突变体也会随着时间的推移而积累。这些拟议的工作室将考虑这些逃逸突变体积累的速度和程度，以确定病毒适应实际上是否可能对当前的 T 细胞疫苗设计产生影响。