CTL and HIV Polymorphisms in Heterosexual Transmission

异性传播中的 CTL 和 HIV 多态性

基本信息

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
项目类别：
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

项目摘要

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）：全世界有超过3000万HIV-1感染的人，每位可以接受抗逆转录病毒疗法（ART）的感染者有4种新感染，仍然存在着制定和部署预防措施的迫切需求，包括微生物剂和预防性疫苗。但是，在人类试验中，基于腺病毒的疫苗的最近失败突显了我们对构成这种迅速发展的病毒的保护性免疫的了解，以及人类如何有效抑制持续的病毒复制。了解宿主免疫反应与自然感染中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生并促进耐耐受的免疫力。该多入侵器应用程序的主要目的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发挥的作用。这将基于对在卢萨卡和赞比亚Ndola招收的信息，最初是HIV-1不一致的夫妇的全面分析。通过评估通过每季度随访的传播和非传播夫妇，我们的调查将实现两个主要目标。首先，我们将通过三种相关机制来确定细胞免疫反应是否影响异性HIV-1的传播：a）在慢性感染的CTL诱导的病毒突变的慢性感染指数伴侣中，具有适应性成本，b）CTL对保守或未突变的病毒表位的反应在Hla-i discorther中均与Hla-discorpters Hla-i Discord cou（比较Hla-i counters of Hla-i Discord cou）（等位基因），c）自然杀手（NK）细胞功能参与传播和非传播夫妇。其次，我们将评估细胞免疫反应可以在改变已知（流行病学上）病毒供体的血清逆变器中对早期HIV-1感染的控制中发挥的作用。这项工作将集中于CTL逃生的途径和动力学，以及在病毒蛋白质组上遍布常规和隐秘表位（由交替阅读框架编码的表位）的恢复。 NK和T-助细胞对控制早期HIV-1遏制的控制的重要性也将进行测试。总的来说，这些全面的多学科研究将在传播后不久和后不久提供有关HIV-1免疫发育的关键基本信息。对HIV-1感染的先天和适应性细胞免疫反应的清晰了解将有助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：了解HIV-1如何与宿主免疫系统相互作用，以免在急性和早期感染期间避免其抑制作用，如果我们要设计预防方法以减少流行病。该提案的目标通过表征先天和适应性细胞反应对传播以及急性/早期感染的影响直接解决了这一问题。对这种病毒宿主相互作用的清晰了解将有助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。