Contribution of anti-env immune responses to protection by live attenuated SIV

尽管针对多种人类病毒的有效疫苗是通过经验性的试错法开发出来的， 在不了解保护性免疫的机制或要求的情况下，HIV-1是不同的。 HIV-1不同于我们以前面对的任何病毒病原体。主要问题在于艾滋病病毒 神秘的能力，以避免宿主的免疫防御，并不断复制，在面对明显强大的 宿主免疫反应在没有偶然发现HIV-1疫苗的情况下， 我们可能需要解决具体的科学障碍来指导我们的道路。首先要 了解什么是需要从疫苗，以实现有效的保护性免疫。实验 在该项目的这一组成部分中提出的建议旨在阐明反 Env免疫反应，特别是中和抗体反应，对所赋予的显著保护作用， 减毒活SIV。主要采用的方法是遗传学方法：免疫恒河猴 将受到克隆的致病性SIV的挑战，这些SIV在特定区域匹配或不匹配。 相对于存在于疫苗株中的序列，本发明的疫苗株的基因组中的核苷酸序列是可变的。在多大程度上， 序列降低了观察到的保护程度？在多大程度上，所有非- Env序列降低了观察到的保护程度？疫苗/攻毒实验 项目2还将采用恒河猴控制SIV疫苗株的实验设计， 缺乏可检测的抗SIV抗体反应。这些系统将用于调查是否 病毒特异性抗体应答对于抵抗同源SIV 239的保护程度是重要的 挑战.定义抗Env反应对保护程度的相对贡献并不是一个简单的方法。 学术兴趣的简单、琐碎的观点。疫苗方法目前正在通过人类 测试没有信封组件，尽管事实上，我们根本不知道有多重要的反环境 响应可以是针对可以实现的保护程度。疫苗/攻毒的结果 项目2中的实验将为包含或省略信封的逻辑提供重要的指导 正在人体试验的疫苗方法的组成部分。

Although effective vaccines for a variety of human viruses were developed by an empirical, trial-and-error approach without knowledge of the mechanisms or requirements for protective immunity, HIV-1 is different. HIV-1 is unlike any viral pathogen that we have faced previously. The principal problem lies in HIV's uncanny ability to avoid host immune defenses and to replicate continuously in the face of apparently-strong host immune responses. In the absence of blind luck in stumbling upon a successful vaccine for HIV-1, it is likely that we will need to solve specific scientific obstacles to guide our way. First and foremost, we must learn what is needed from a vaccine in order to achieve effective protective immunity. The experiments proposed in this component of the program project are directed at elucidating the relative contribution of anti- Env immune responses, particularly neutralizing antibody responses, to the remarkable protection conferred by live-attenuated SIV. The principal approach to be used is a genetic one: immunized rhesus macaques will be challenged with cloned pathogenic SIVs that are matched or mismatched in particular regions of the genome relative to the sequences present in the vaccine strain. To what extent does a mismatch of Env sequences decrease the degree of protection that is observed? To what extent does a mismatch of all non- Env sequences decrease the degree of protection that is observed? Vaccine/challenge experiments in Project 2 will also employ experimental designs by which rhesus macaques control the SIV vaccine strain in the absence of detectable anti-SIV antibody responses. These systems will be used to investigate whether viral-specific antibody responses are important for the degree of protection against homologous SIV239 challenge. Defining the relative contribution of anti-Env responses to the degree of protection is not a simple, trivial point of academic interest. Vaccine approaches are currently advancing through human testing without an Envelope component despite the fact that we simply do not know how important anti-Env responses may be for the degree of protection that can be achieved. The outcomes of the vaccine/challenge experiments in Project 2 will provide important guidance on the logic of including, or omitting, Envelope components for vaccine approaches being tested in people.