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）：全世界有3 000多万艾滋病毒-1感染者，每有1名感染者可以接受抗逆转录病毒治疗（ART），就有4名新感染者，因此仍然迫切需要制定和部署预防措施，包括杀微生物剂和预防性疫苗。然而，最近一种基于CTL诱导腺病毒的疫苗在人体试验中失败，突显出我们缺乏对这种快速进化的病毒的保护性免疫构成的理解，以及人类如何有效地抑制正在进行的病毒复制。了解自然感染中宿主免疫反应与病毒之间的相互作用对于设计新的策略来规避病毒免疫逃逸和促进持久免疫至关重要。这个多研究者应用的主要目标是详细定义先天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起的作用。这将基于对在赞比亚卢萨卡和恩多拉登记的信息丰富的、最初感染艾滋病毒不一致的夫妇的全面分析。通过每季度随访评估传播和非传播夫妇，我们的调查将追求两个主要目标。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恋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与适应成本，b)在hla - 1不一致的伴侣中暴露和未感染的伴侣中（与那些共享hla - 1等位基因的伴侣相比），CTL对保守或未突变的病毒表位的反应，c)自然杀伤（NK）细胞功能在传递和非传递伴侣中的参与。其次，我们将评估细胞免疫反应在改变控制已知（流行病学相关）病毒供体的血清转化者的早期HIV-1感染中所起的作用。这项工作将重点关注病毒蛋白质组中常规表位和隐表位（由交替阅读框编码的表位）的CTL逃逸和逆转的途径和动力学。NK和t辅助细胞对早期HIV-1控制的重要性也将被测试。总的来说，这些综合性和多学科的研究将提供关于HIV- 1在传播时和传播后不久的免疫发病机制的关键基础信息。清楚地了解对HIV-1感染的先天和适应性细胞免疫反应将有利于开发预防工具，从而减少HIV-1感染的进一步传播。