CTL and HIV Polymorphisms in Heterosexual Transmission

描述（由申请人提供）：全世界有超过3000万HIV-1感染者，每4名新感染者中就有1名可以接受抗逆转录病毒治疗（ART），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，最近在人体试验中基于CTL诱导的腺病毒疫苗的失败突出了我们对什么构成针对这种快速进化的病毒的保护性免疫以及人类如何能够有效地抑制正在进行的病毒复制缺乏了解。了解宿主免疫反应和病毒在自然感染中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不一致的夫妇进行的全面分析。通过每季度对传播和非传播夫妇进行随访评估，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HIV-1的异性传播：a）CTL诱导的病毒突变在慢性感染的索引伴侣中的积累，具有适应性成本，B）在HLA-I不一致的夫妇中，CTL对暴露和未感染的伴侣中的保守或未突变的病毒表位的应答（与共享HLA-I等位基因的那些相比），c）自然杀伤（NK）细胞功能在传递和非传递夫妇中的参与。第二，我们将评估细胞免疫应答在改变已知（流行病学相关）病毒供体血清转换者早期HIV-1感染控制中的作用。这项工作将集中在途径和动力学的CTL逃逸和逆转的传统和隐蔽表位（表位编码的替代阅读框架）在整个病毒蛋白质组。NK细胞和辅助性T细胞对控制早期HIV-1感染的重要性也将得到检验。总的来说，这些综合性和多学科的研究将提供关键的基本信息，艾滋病毒- 1的免疫发病机制的时间和传播后不久。对HIV-1感染的先天性和适应性细胞免疫反应的清楚理解将有利于开发预防工具的最终目标，这些工具可以减少HIV-1感染的进一步传播。

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.