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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）：CD 8 + T细胞T细胞可以在HIV感染的免疫控制中发挥核心作用。然而，为了达到最佳效果，HIV疫苗应该诱导的CD 8 + T细胞应答尚未建立。我们在过去5年中所做的工作主要集中在南部非洲的艾滋病毒流行，该地区受艾滋病毒影响最严重，最迫切需要有效的疫苗。从我们在过去5年中所做的工作中可以得出的一个主要结论是，HIV感染的免疫控制是由广泛的Gag特异性CD 8 + T细胞应答促进的，特别是Gag中的应答，但在较小程度上也是Pol中的应答，这可以驱动对病毒的选择压力。很明显，一些最有效的反应对其他无效的反应是次显性的。表位功效在蛋白质之间不同（Gag>Pol>Acc-Reg>Env），但在蛋白质内也不同。表位功效也根据HLA限制而不同。HLA-B限制性应答对病毒设定点的影响最大，并对病毒产生最强的选择压力。HLA-C限制性应答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的目标是，使用一种新的方法来实现CTL表位的快速定义，以确定这些反应，包括亚显性反应，在Gag和Pol中，最有效地抑制HIV复制。很明显，目前对靶向的最佳表位和CD 8 + T细胞应答层次的了解，即使对于最普遍的HLA等位基因，仍然不足以理解自然HIV感染中的CD 8 + T细胞应答，以及可能需要对该应答层次进行什么样的扰动来优化CD 8 + T细胞对HIV免疫控制的贡献。对于存在于1/6的南部非洲人群中的等位基因如A*6802，目前描述的最佳表位仅占受该等位基因限制的A*6802阳性受试者的实际应答的1%。新的方法，涉及使用肽-MHC四聚体，是快速和廉价的，已被我们验证，如在初步数据中所示，至关重要的是提供了进一步的机会，以评估纯化的抗原特异性细胞在病毒抑制试验中的功效。这些研究的第二个目的是研究人类T细胞疫苗改变自然感染中观察到的反应层次的能力。我们将研究接种了表达Gag、Pol和Nef的MRK Ad 5疫苗（HVTN 503，“Phambili”研究）的南非受试者。使用我们的1，015名南非研究受试者的数据库，我们使用410个重叠18聚体肽的小组表征了针对C进化枝感染的CD 8 + T细胞应答，我们将能够确定这种MRK Ad 5 T细胞疫苗是否已经显示出在感染后疫苗接种者中特异性增强Gag，Pol和Nef应答，可以改变未接种疫苗的感染者的反应层次。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的是研究病毒适应对CD 8 + T细胞应答层次的影响。我们在过去5年的工作中已经表明，病毒适应是在群体水平上发生的，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。这些逃逸突变体积累的速度和程度将在这些拟议的研究中考虑，以确定病毒适应是否可能对目前的T细胞疫苗设计产生影响。