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

• 批准号: 8130799
• 负责人: Hendrik Streeck
• 金额: $ 53.37万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-18 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8130799
• 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

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例新的艾滋病毒-1感染，这突出表明迫切需要研制一种艾滋病毒-1疫苗。尽管我们对HIV-1感染的体液和细胞免疫反应的理解取得了重大进展，但保护的相关因素仍未确定。最近默克疫苗试验的失败，以及使用ALVAC-HIV （vCP1521）与AIDSVAX B/E主要增强组合的RV144 HIV疫苗试验的意外成功，挑战了我们对保护性疫苗构成的概念。引人注目的是，疫苗不仅诱导了强烈的抗体反应，而且还诱导了强烈的hiv -1特异性CD4+ T细胞反应。迄今为止，诱导HIV-1特异性CD4+ T细胞反应的方法一直受到质疑，因为这些尝试可能会扩大HIV-1特异性CD4+ T细胞靶点的数量。然而，在淋巴脉络丛脑膜炎病毒（LCMV）小鼠模型中令人信服的研究表明，病毒特异性白细胞介素-21 （IL21）分泌CD4+ T细胞应答是建立有效和长期的病毒特异性免疫的关键因素。缺乏il - 21或il - 21受体（IL21R）的小鼠更容易发生慢性LCMV感染。IL21+CD4+ T细胞反应已被证明可增强病毒特异性CD8+ T细胞的细胞毒性，并可直接转换抗体类别和激活B细胞。因此，il - 21+CD4+ T细胞应答在病毒特异性免疫的协调中起着核心作用。令人惊讶的是，人们对il - 21+ CD4+ 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，HIV-1特异性il - 21+CD4+ T细胞反应在HIV-1精英控制者中存在，并优先靶向Gag蛋白内的表位。相比之下，在慢性进行性HIV-1感染的受试者中，几乎没有检测到IL21+CD4+ T细胞反应。此外，我们有证据表明，IL21信号可以将非控制性CD8+ T细胞反应转化为具有强抑制活性的CD8+ T细胞反应。因此，我们的初步数据表明，il - 21+CD4+ T细胞反应可能是产生有效的CD8+ T细胞或B细胞疫苗的关键因素。具体来说，我们建议：1)确定hiv -1特异性IL21+CD4+ 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)。评估hiv -1特异性IL21+CD4+ T反应如何调节hiv -1特异性CD8+ T细胞并增强其抑制病毒复制的能力。4)。研究靶向治疗性CD4疫苗是否能诱导这种反应，最后5)评估il - 21+CD4+ T细胞如何调节hiv -1特异性B细胞功能。该建议的基本假设是，hiv -1特异性IL21+ CD4+ 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CD8+ T细胞的抑制活性，在控制病毒复制中起关键作用。在预防性或治疗性疫苗中诱导和繁殖这些反应对于长期有效的病毒特异性免疫至关重要。