CTL and HIV Polymorphisms in Heterosexual Transmission

异性传播中的 CTL 和 HIV 多态性

• 批准号: 8069728
• 负责人: Paul A. Goepfert
• 金额: $ 25.06万
• 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: 2010-05-17 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8069728
• 关键词: Acute; Address; Adenoviruses; Age; Alleles; Anti-Retroviral Agents; CD4 Positive T Lymphocytes; Cell physiology; Containment; Couples; Developing Countries; Employee Strikes; Enrollment; Epidemic; Epitopes; Failure; Family; Genetic Polymorphism; Goals; HIV; HIV-1; Haplotypes; Helper-Inducer T-Lymphocyte; Heterosexuals; Human; Human Virus; Immune; Immune response; Immune system; Immunity; In Vitro; Individual; Infection; Infection prevention; Investigation; Killer Cells; Kinetics; Ligands; Link; Measures; Mediating; Mutate; Mutation; Natural Killer Cells; Nature; Pathway interactions; Persons; Play; Prevention approach; Preventive; Process; Proteome; Reading Frames; Receptor Gene; Research Personnel; Role; Sampling; Sexually Transmitted Diseases; Testing; Time; Vaccines; Viral; Virus; Virus Replication; Visit; Work; Zambia; base; cohort; cost; design; fitness; follow-up; gag Gene Products; in vivo; indexing; killer inhibitory receptor; microbicide; multidisciplinary; novel strategies; pressure; prevent; prophylactic; public health relevance; response; tool; transmission process

DESCRIPTION (provided by applicant): With over 30 million HIV-1 infected individuals worldwide, and a rate of 4 new infections for every infected person who can receive anti-retroviral therapy (ART), there is still a critical need for developing and deploying preventive measures, including microbicides and prophylactic vaccines. However, the recent failure of a CTL- inducing adenovirus-based vaccine in human trials highlights our lack of understanding of what constitutes a protective immunity against this rapidly evolving virus, and how humans can effectively suppress ongoing virus replication. Understanding the interplay between the host immune response and the virus in natural infection is essential to designing novel strategies for circumventing viral immune escape and promoting endurable immunity. The major goal of this multi-investigator application is to define in detail the role that the innate and adaptive cellular immune systems play in modulating the process of HIV-1 transmission and viral control. This will be based on a comprehensive analyses of informative, initially HIV-1 discordant couples enrolled in Lusaka and Ndola, Zambia. By evaluating transmitted and non-transmitting couples with quarterly follow-up visits, our investigation will pursue two main goals. First, we will determine whether cellular immune responses influence heterosexual HIV-1 transmission through three related mechanisms: a) accumulation in the chronically infected index partners of CTL-induced viral mutations with fitness costs, b) the CTL response to conserved or un- mutated viral epitopes in exposed and uninfected partners among HLA-I discordant couples (compared to those that share HLA-I alleles), c) involvement of natural killer (NK) cell function in transmitting and non- transmitting couples . Second, we will assess the role that cellular immune responses can play in modifying control of early HIV-1 infection in seroconverters with known (epidemiologically-linked) virus donors. This work will focus on pathways and kinetics of CTL escape and reversion of both conventional and cryptic epitopes (epitopes encoded by alternate reading frames) across the viral proteome. The importance of NK and T-helper cell to the control of early HIV-1 containment will be tested as well. Collectively, these comprehensive and multidisciplinary studies will provide critical basic information about HIV- 1 immunopathogenesis at the time of and shortly after transmission. A clear understanding of innate and adaptive cellular immune responses to HIV-1 infection will benefit the ultimate goal of developing preventive tools that can reduce the further spread of HIV-1 infection. PUBLIC HEALTH RELEVANCE: Understanding how HIV-1 interacts with the host immune system in order to escape its inhibitory effects during acute and early infection is critical if we are to devise preventive approaches to reduce the epidemic. The goals of this proposal address this problem directly by characterizing the impact of both the innate and adaptive cellular responses on transmission and acute/early infection. A clear understanding of this virus-host interplay will benefit the ultimate goal of developing preventive tools that can reduce the further spread of HIV- 1 infection.

描述（由申请人提供）：全球有超过 3000 万 HIV-1 感染者，并且每一个可以接受抗逆转录病毒治疗 (ART) 的感染者就有 4 例新感染，仍然迫切需要开发和部署预防措施，包括杀微生物剂和预防性疫苗。然而，最近基于 CTL 诱导的腺病毒疫苗在人体试验中的失败凸显了我们对这种快速进化的病毒的保护性免疫力的构成以及人类如何有效抑制持续的病毒复制缺乏了解。了解自然感染中宿主免疫反应和病毒之间的相互作用对于设计规避病毒免疫逃逸和促进持久免疫的新策略至关重要。这项多研究者应用的主要目标是详细定义先天性和适应性细胞免疫系统在调节 HIV-1 传播和病毒控制过程中所发挥的作用。这将基于对赞比亚卢萨卡和恩多拉登记的信息丰富、最初 HIV-1 不一致的夫妇的全面分析。通过每季度的随访来评估传播性和非传播性夫妇，我们的调查将实现两个主要目标。首先，我们将确定细胞免疫反应是否通过三种相关机制影响异性 HIV-1 传播：a）CTL 诱导的病毒突变在慢性感染指数伴侣中的积累，以及适应度成本；b）CTL 对保守或未突变的反应HLA-I 不一致夫妇中暴露和未感染伴侣的病毒表位（与共享 HLA-I 等位基因的夫妇相比），c) 自然杀伤 (NK) 细胞功能在传播和非传播夫妇中的参与。其次，我们将评估细胞免疫反应在改变已知（流行病学相关）病毒供体的血清转化者中早期 HIV-1 感染的控制方面所发挥的作用。这项工作将重点关注病毒蛋白质组中常规表位和隐藏表位（由交替阅读框编码的表位）的 CTL 逃逸和回复的途径和动力学。 NK 和 T 辅助细胞对于控制早期 HIV-1 遏制的重要性也将得到测试。总的来说，这些全面的多学科研究将提供有关 HIV-1 传播时和传播后不久的免疫发病机制的重要基本信息。清楚地了解对 HIV-1 感染的先天性和适应性细胞免疫反应将有利于开发预防工具的最终目标，以减少 HIV-1 感染的进一步传播。 公共卫生相关性：如果我们要制定预防方法来减少流行病，那么了解 HIV-1 如何与宿主免疫系统相互作用以逃避其在急性和早期感染期间的抑制作用至关重要。该提案的目标是通过描述先天性和适应性细胞反应对传播和急性/早期感染的影响来直接解决这个问题。清楚地了解这种病毒与宿主的相互作用将有利于开发预防工具的最终目标，以减少 HIV-1 感染的进一步传播。