CTL and HIV Polymorphisms in Heterosexual Transmission

描述(申请人提供)：全世界有3000多万艾滋病毒-1感染者，每接受抗逆转录病毒疗法(ART)的感染者新感染率为4人，仍然迫切需要制定和部署预防措施，包括杀菌剂和预防性疫苗。然而，最近CTL诱导腺病毒疫苗在人体试验中的失败突显了我们对这种快速进化的病毒的保护性免疫是什么构成的缺乏了解，以及人类如何有效地抑制正在进行的病毒复制。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新的策略来规避病毒免疫逃逸和促进持久免疫是至关重要的。这一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发挥的作用。这将基于对在赞比亚卢萨卡和恩多拉登记的信息丰富的、最初是艾滋病毒-1不和谐的夫妇的全面分析。通过对传播性和非传播性夫妇进行季度随访评估，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诱导的病毒突变的慢性感染指数伴侣中的累积，以及适合性成本；b)接触和未感染伴侣中对保守或未突变病毒表位的CTL反应(与那些具有相同的HLA-I等位基因的夫妇相比)；c)自然杀伤(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在改变对已知(流行病学上有关联的)病毒供体的血清转换者早期HIV-1感染的控制中所起的作用。这项工作将集中在传统表位和隐蔽表位(由交替阅读框编码的表位)跨越病毒蛋白质组的CTL逃逸和逆转的途径和动力学。NK和T辅助细胞对控制早期HIV-1遏制的重要性也将得到测试。总体而言，这些全面和多学科的研究将提供有关艾滋病毒-1在传播时和传播后不久免疫病理机制的关键基本信息。清楚地了解对艾滋病毒-1感染的先天和适应性细胞免疫反应将有助于开发能够减少艾滋病毒-1感染进一步传播的预防工具的最终目标。

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.