CTL AND HIV POLYMORPHISMS IN HETEROSEXUAL TRANSMISSION

异性传播中的 CTL 和 HIV 多态性

• 批准号: 8172394
• 负责人: Eric Hunter
• 金额: $ 5.48万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172394
• 关键词: African; Alleles; Antiviral Agents; Attenuated; Chronic; Cohort Studies; Computer Retrieval of Information on Scientific Projects Database; Cross-Sectional Studies; Data; Disease Outcome; Environment; Epitopes; Frequencies; Funding; Gagging; Genetic Polymorphism; Genome; Grant; HIV; HIV-1; Heterosexuals; Immune; Immune response; Immunity; Immunogenetics; In Vitro; Infection; Institution; Kinetics; Mutate; Mutation; Population; Property; Proteins; Reading Frames; Research; Research Personnel; Resources; Role; Source; South Africa; Staging; Transcript; United States National Institutes of Health; Vaccines; Variant; Viral; Viral Load result; Virus; Zambia; cohort; immunogenic; in vivo; nef Genes; pressure; response; transmission process

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Objectives: Perform cross-sectional analysis of HIV adaptation to HLA-class I restricted immune responses; determine kinetics of CTL epitope escape/reversion in 150 transmission pairs as virus adapts in moving from one immunogenetic environment to another; determine if long-term non-transmitting partners display bias in escape signatures that contribute to lack of transmission. In two HIV C clade-infected populations in South Africa/Zambia, we sought to elucidate the role of HLA-B*5703 in HIV disease outcome. HLA-B*5703-restricted CTL responses select for escape mutations in three Gag p24 epitopes, in predictable order. We show accumulation of these mutations sequentially reduces viral replicative capacity in vitro. Despite this, in-vivo data demonstrate that there is ultimately an increase in viral load concomitant with evasion of all three HLA-B*5703-restricted CTL responses. These data demonstrate that, although costly escape from CTL responses can progressively attenuate the virus, high viral loads develop in absence of adequate, continued CTL responses. At least some alternate reading frames in HIV-1 have potential to encode proteins of unknown function, and their antigenic properties can be considered as cryptic epitopes (CEs). We analyzed HLA class I-associated polymorphisms in HIV-1 gag, pol, and nef genes from a large cohort of South Africans with chronic infection. In all, 391 CEs and 168 conventional epitopes were predicted, with majority derived from antisense transcripts. Both sense- and antisense-encoded CEs were immunogenic at both stages of infection. In addition, CEs often mutated during first year of infection, which was consistent with immune selection for escape variants. These findings indicate that HIV-1 genome might encode and deploy a large potential repertoire of unconventional epitopes to enhance vaccine-induced antiviral immunity. Finally, results from a 9-cohort study showed the frequency of certain epitope variants was highly correlated with the abundance of the restricting HLA allele, suggesting viral adaptation to HLA pressure within the population.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 目标：对 HIV 对 HLA-I 类限制性免疫反应的适应进行横断面分析；当病毒适应从一种免疫遗传环境转移到另一种免疫遗传环境时，确定 150 个传播对中 CTL 表位逃逸/回复的动力学；确定长期不传播的伴侣是否在导致缺乏传播的逃逸特征中表现出偏见。 在南非/赞比亚的两个 HIV C 分支感染人群中，我们试图阐明 HLA-B*5703 在 HIV 疾病结果中的作用。 HLA-B*5703 限制性 CTL 反应以可预测的顺序选择三个 Gag p24 表位中的逃逸突变。我们发现这些突变的积累会依次降低病毒的体外复制能力。尽管如此，体内数据表明，随着逃避所有三种 HLA-B*5703 限制性 CTL 反应，病毒载量最终会增加。这些数据表明，尽管逃避 CTL 反应的代价高昂，可以逐渐减弱病毒，但在缺乏充分、持续的 CTL 反应的情况下，会产生高病毒载量。 HIV-1 中至少有一些替代阅读框有可能编码未知功能的蛋白质，并且它们的抗原特性可以被视为隐性表位 (CE)。我们分析了来自一大群患有慢性感染的南非人的 HIV-1 gag、pol 和 nef 基因的 HLA I 类相关多态性。总共预测了 391 个 CE 和 168 个常规表位，其中大部分来自反义转录本。有义和反义编码的CE在感染的两个阶段均具有免疫原性。此外，CE经常在感染的第一年发生突变，这与逃逸变异的免疫选择是一致的。这些发现表明，HIV-1 基因组可能编码和部署大量潜在的非常规表位，以增强疫苗诱导的抗病毒免疫。 最后，一项 9 队列研究的结果表明，某些表位变异的频率与限制性 HLA 等位基因的丰度高度相关，表明病毒对人群中 HLA 压力的适应。