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：
8070823
负责人：
PHILIP J GOULDER
金额：
$ 47.31万
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 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8070823
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

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

展开

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. PUBLIC HEALTH RELEVANCE: CD8+ T-cell responses play an important part in successful immune control of HIV infection. However, it remains unclear what T-cell responses need to be induced by a vaccine in order to optimise immune control of HIV in post-infection vaccines. These proposed studies, focusing on the HIV epidemic in southern Africa, aim to use a novel approach to rapidly define and characterize epitopes in Gag and Pol which, if induced by a vaccine, might be expected to improve immune control significantly, compared to HLA matched individuals with natural HIV infection. In the second part of the studies, we will study the T cell responses of South Africans who became infected having received the MRK Ad 5 T-cell vaccine, to determine whether this vaccine, which expressed Gag, Pol and Nef, had been able in selected study subjects to alter the CD8+ T-cell response hierarchy. Finally, we aim to address the impact of viral adaptation on the CD8+ T-cell response hierarchy, in order to determine whether viral adaptation which is detectable, is sufficiently rapid and extensive to affect the epitopes that currently are most successful at inhibition of viral replication.

描述（由申请人提供）：CD8+ T细胞T细胞在HIV感染的免疫控制中可能是核心作用。但是，为了最佳有效，应由HIV疫苗诱导的CD8+ T细胞反应尚未确定。我们在这笔赠款的前5年中所做的工作集中在南部非洲的艾滋病毒流行病上，该地区受艾滋病毒影响最严重，最迫切需要有效的疫苗。从我们在这笔赠款的过去5年中所做的工作中可以得出的一个重大结论是，对艾滋病毒感染的免疫控制是由广泛的GAG特异性CD8+ T细胞反应促进的，特别是通过GAG的反应，但在POL的程度较小，可以驱动病毒的选择压力。显然，某些最有效的反应是其他无效反应的亚军。表位功效在蛋白质（gag> pol> acc-reg> env）之间，但在蛋白质内也有所不同。表位功效也与HLA限制不同。 HLA-B限制反应对病毒设定点具有最大的影响，并驱动了对病毒的最大选择压力。 HLA-C限制的响应即使特异性GAG特异性也与高病毒设定值有关。这些提出的研究的第一个具体目的的目标是，使用一种新的方法来快速地定义CTL表位，以识别最有效地抑制HIV复制的GAG和POL中的这些反应，包括亚抑制反应。很明显，当前对最佳表位的知识以及CD8+ T细胞的响应层次结构，即使是最普遍的HLA等位基因，也仍然不足以了解自然HIV感染中的CD8+ T细胞反应，并且可能需要该反应层次的哪些扰动来优化CD8+ T-CELL CORMATION dymune premune formime formune formune formune formune formune formune formune formime h都是H h。对于像A*6802这样的等位基因，目前描述的是南部非洲人口的1/6，仅占A*6802阳性受试者的实际反应的1％，而该反应受该Alelle限制的。这种新方法涉及使用肽-MHC四聚体的使用快速且廉价的方法，已由我们验证，如提出的初步数据所示，并至关重要的是提供了进一步的机会来评估纯化的抗原特异性细胞在病毒抑制分析中的功效。这些研究的第二个目的是研究人类中T细胞疫苗改变自然感染中观察到的反应层次结构的能力。我们将研究以MRK AD5疫苗接种疫苗的南非受试者（HVTN 503，“ Phambili”研究），该研究表达了GAG，POL和NEF。使用我们的1,015个南非研究对象的数据库，我们使用410个重叠18mer肽的小组对C型进化剂感染的CD8+ T细胞响应进行了表征，我们将能够确定该MRK AD5 T-CELL疫苗是否已经表明，该疫苗是否已被证明，该疫苗是否已被证明，该疫苗是否已被证明，该疫苗已被证明是针对以下响应，POL和NEF的反应率，该反应率是较高的，POL和NEF的反应率，以供应效果，并在此反应率，并在此反应率，并在此反应率。未接种疫苗感染的人。这将是T细胞疫苗有效的重要先决条件。这些提出的研究的最终具体目的是研究病毒适应对CD8+ T细胞反应层次结构的影响。在过去的5年中，我们已经表明，病毒适应在人群水平上发生，即使最保护性表位中的逃生突变体随着时间的流逝而积累。这些提议的工作室将考虑这些逃生突变体积累的速度以及在多大程度上，以确定实际上病毒适应是否可能对当前的T细胞疫苗设计产生影响。公共卫生相关性：CD8+ T细胞反应在成功控制HIV感染的免疫控制中起着重要作用。但是，目前尚不清楚疫苗需要诱导哪些T细胞反应，以优化感染后疫苗中对HIV的免疫控制。这些提出的研究侧重于南部非洲的HIV流行，旨在使用一种新颖的方法来快速定义和表征GAG和POL中的表位，如果疫苗诱导，与HLA匹配的自然HIV感染相比，可能会显着改善免疫控制。在研究的第二部分中，我们将研究南非人的T细胞反应，这些T细胞的反应被感染后接受了MRK AD 5 T细胞疫苗，以确定该疫苗（表达GAG，POL和NEF）是否能够在选定的研究主题中改变CD8+ T-Cell响应率。最后，我们旨在解决病毒适应对CD8+ T细胞响应层次结构的影响，以确定是否可以检测到的病毒适应性是否足够快，并且广泛地影响了当前在抑制病毒复制方面最成功的表位。