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Modulation of HIV-specific CD8+ T and B cell function by CD4+ T helper responses

CD4 T 辅助反应对 HIV 特异性 CD8 T 和 B 细胞功能的调节

基本信息

批准号：
8513900
负责人：
Hendrik Streeck
金额：
$ 30.26万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
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：
2010-08-18 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8513900
关键词：
ALVAC Acquired Immunodeficiency Syndrome Anti-Retroviral Agents Antibodies Antibody Formation Antigens Antiviral Agents Autoimmune Diseases B-Cell Activation B-Lymphocytes Biological Preservation CD4 Positive T Lymphocytes CD8B1 gene Cell physiology Cessation of life Chronic Combined Vaccines Communicable Diseases Data Development Epitopes Exclusion Failure Generations HIV HIV Infections HIV vaccine HIV-1 Helper-Inducer T-Lymphocyte Highly Active Antiretroviral Therapy Human Immune Immune response Immune system Immunity Immunoglobulin Class Switching Individual Infection Life Mediator of activation protein Mus Play Predisposition Production Recording of previous events Reporting Role Signal Transduction Specificity T cell response T-Lymphocyte Therapeutic Vaccination Vaccine Design Vaccine Research Vaccines Viral Viral Load result Virus Virus Diseases base cost cytotoxicity gag Gene Products interleukin-21 interleukin-21 receptor meetings memory CD4 T lymphocyte mouse model pandemic disease pathogen prophylactic public health relevance response success theories therapeutic vaccine vaccine candidate

项目摘要

DESCRIPTION (provided by applicant): An estimate 6,800 new HIV-1 infections daily dramatically underscores the desperate need for the development of an HIV-1 vaccine. Despite significant advances in our understanding of both the humoral and cellular immune response in HIV-1 infection, the correlates of protection have still not been defined. The recent failure of the Merck vaccine trial and the unexpected modest success of the RV144 HIV vaccine trial using ALVAC-HIV (vCP1521) in a prime boost combination with AIDSVAX B/E, have challenged our notion of what constitutes a protective vaccine. Strikingly, the vaccine induced not only strong antibody responses, but also a robust HIV-1-specific CD4+ T cell response. Approaches to induce HIV-1-specific CD4+ T cell responses have been met with skepticism thus far as these attempts may expand the pool of HIV-1 specific CD4+ T cells targets. However, compelling studies in the lymphochoriomeningitis virus (LCMV) mouse model suggest that virus-specific Interleukin-21 (IL21) secreting CD4+ T cell responses are a critical key factor to establish effective and long-lived virus-specific immunity. Mice lacking IL21 or IL21 receptor (IL21R) were more susceptible to chronic LCMV infection. IL21+CD4+ T cell responses have been shown to enhance cytotoxicity of virus-specific CD8+ T cells and direct antibody class switching and activation of B cells. Thus, IL21+CD4+ T cell responses play a central role in the coordination of virus-specific immunity. Surprisingly little is known about the role of IL21+ CD4+ T cells in human viral infections. Our preliminary data suggest that robust HIV-1- specific IL21+CD4+ T cell responses exist in HIV-1 elite controllers with a preferential targeting of epitopes within the Gag protein. In contrast, in subjects with chronic-progressive HIV-1 infection virtually no IL21+CD4+ T cell responses are detectable. Moreover, we have evidence that IL21 signals can transform non-controlling CD8+ T cell responses into CD8+ T cell responses with strong inhibitory activity. Thus, our preliminary data suggest that IL21+CD4+ T cell responses might be a critical factor for the generation of an effective CD8+ T cell or B cell based vaccine. Specifically we propose to: 1) Determine the presence and specificity of HIV-1-specific IL21+CD4+ T cells as well as their role in the control of viral replication. 2) Determine whether early antiretroviral treatment in primary HIV-1 infection preserves these particular responses. 3.) Assess how HIV-1-specific IL21+CD4+ T responses modulate HIV-1-specific CD8+ T cells and enhance their capacity to inhibit viral replication. 4.) Investigate whether therapeutic CD4-targeted vaccination can induce such responses and finally 5.) assess how IL21+CD4+ T cells modulate HIV-1-specific B cell functions. The underlying hypotheses of this proposal are that HIV-1-specific IL21+ CD4+ T cells have a key function in the control of viral replication by modulating HIV-1-specific B cell function and increasing the inhibitory activity of HIV-1-specific CD8+ T cells. The induction and propagation of these responses in a prophylactic or therapeutic vaccine will be essential for long-lived effective virus-specific immunity. PUBLIC HEALTH RELEVANCE: With 33 million HIV-1 infected individuals world-wide an HIV-1 vaccine is urgently needed. The recent failure of the Merck vaccine trial and the unexpected modest success of a vaccine consisting of a combination of two vaccine candidates (ALVAC/AIDSVAX; "Thai trial") drastically demonstrate our poor understanding how to develop an effective vaccine. Strikingly, the used vaccine not only induced antibodies, but also a robust HIV-1-specific CD4+ T cell response. Recent data from the mouse model suggest that virus-specific Interleukin-21 (IL21)-secreting CD4+ T cell responses are critical to support virus-specific CD8+ T cell and B cell immunity. Thus in this proposal we aim to define the role of HIV-1-specific IL21+CD4+ T cell responses in the control of HIV-1 infection to determine whether the induction of these responses should be a key component of a prophylactic and therapeutic vaccine.

描述（由申请人提供）：估计每天有6，800例新的HIV-1感染，这突出了开发HIV-1疫苗的迫切需要。尽管我们对HIV-1感染中的体液和细胞免疫应答的理解有了重大进展，但保护的相关性仍然没有被确定。最近默克疫苗试验的失败和使用ALVAC-HIV（vCP 1521）与AIDSVAX B/E联合初免加强的RV 144 HIV疫苗试验的意外适度成功，挑战了我们关于什么是保护性疫苗的概念。引人注目的是，该疫苗不仅诱导了强烈的抗体应答，而且还诱导了强烈的HIV-1特异性CD 4 + T细胞应答。迄今为止，诱导HIV-1特异性CD 4 + T细胞应答的方法一直受到怀疑，因为这些尝试可能扩大HIV-1特异性CD 4 + T细胞靶标的库。然而，在淋巴脉络丛脑膜炎病毒（LCMV）小鼠模型中进行的令人信服的研究表明，分泌病毒特异性白细胞介素-21（IL 21）的CD 4 + T细胞反应是建立有效且长寿的病毒特异性免疫的关键因素。缺乏IL 21或IL 21受体（IL 21 R）的小鼠更容易受到慢性LCMV感染。已显示IL 21 + CD 4 + T细胞应答增强病毒特异性CD 8 + T细胞的细胞毒性并指导抗体类别转换和B细胞的活化。因此，IL 21 + CD 4 + T细胞应答在病毒特异性免疫的协调中发挥核心作用。令人惊讶的是，关于IL 21 + CD 4 + T细胞在人类病毒感染中的作用知之甚少。我们的初步数据表明，强大的HIV-1特异性IL 21 + CD 4 + T细胞反应存在于HIV-1精英控制者中，优先靶向Gag蛋白内的表位。相比之下，在慢性进展性HIV-1感染的受试者中，几乎检测不到IL 21 + CD 4 + T细胞反应。此外，我们有证据表明IL 21信号可以将非控制性CD 8 + T细胞应答转化为具有强抑制活性的CD 8 + T细胞应答。因此，我们的初步数据表明，IL 21 + CD 4 + T细胞应答可能是产生有效的基于CD 8 + T细胞或B细胞的疫苗的关键因素。具体而言，我们建议：1）确定HIV-1特异性IL 21 + CD 4 + T细胞的存在和特异性以及它们在控制病毒复制中的作用。2)确定原发性HIV-1感染的早期抗逆转录病毒治疗是否保留了这些特殊的反应。3.）第三章评估HIV-1特异性IL 21 + CD 4 + T应答如何调节HIV-1特异性CD 8 + T细胞并增强其抑制病毒复制的能力。4.）研究治疗性CD 4靶向疫苗接种是否可以诱导这种反应，最后5.）评估IL 21 + CD 4 + T细胞如何调节HIV-1特异性B细胞功能。该提议的基本假设是HIV-1特异性IL 21 + CD 4 + T细胞通过调节HIV-1特异性B细胞功能和增加HIV-1特异性CD 8 + T细胞的抑制活性在控制病毒复制中具有关键功能。在预防性或治疗性疫苗中这些应答的诱导和传播对于长期有效的病毒特异性免疫是必不可少的。公共卫生相关性：全世界有3300万HIV-1感染者，迫切需要HIV-1疫苗。最近默克疫苗试验的失败和由两种候选疫苗组合组成的疫苗（ALVAC/AIDSVAX;“泰国试验”）的意外适度成功彻底证明了我们对如何开发有效疫苗的理解不足。引人注目的是，使用的疫苗不仅诱导抗体，而且还诱导了强烈的HIV-1特异性CD 4 + T细胞应答。来自小鼠模型的最新数据表明，分泌病毒特异性白细胞介素-21（IL 21）的CD 4 + T细胞应答对于支持病毒特异性CD 8 + T细胞和B细胞免疫是至关重要的。因此，在本提案中，我们的目标是定义HIV-1特异性IL 21 + CD 4 + T细胞应答在控制HIV-1感染中的作用，以确定这些应答的诱导是否应该是预防性和治疗性疫苗的关键组成部分。