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: 8305995
• 负责人: Hendrik Streeck
• 金额: $ 9.44万
• 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 2012-09-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8305995
• 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）：每天有6,800种新的HIV-1感染大幅度强调了对HIV-1疫苗开发的迫切需求。尽管我们对HIV-1感染中的体液和细胞免疫反应的理解取得了重大进展，但仍未定义保护的相关性。默克疫苗试验的最新失败以及使用ALVAC-HIV（VCP1521）与Aidsvax B/E结合使用ALVAC-HIV（VCP1521）的RV144 HIV疫苗试验的意外中度失败，对我们构成保护性疫苗的概念提出了挑战。令人惊讶的是，疫苗不仅诱导了强抗抗体反应，还诱导了强大的HIV-1特异性CD4+ T细胞反应。诱导HIV-1特异性CD4+ T细胞反应的方法已经对这些尝试扩大了HIV-1特异性CD4+ T细胞靶标的怀疑。然而，在淋巴细胞神经脑膜炎病毒（LCMV）小鼠模型中的引人入胜的研究表明，分泌CD4+ T细胞反应的病毒特异性白细胞介素21（IL21）是建立有效且寿命长的病毒特异性免疫的关键关键因素。缺乏IL21或IL21受体（IL21R）的小鼠更容易受到慢性LCMV感染的影响。 IL21+ CD4+ T细胞反应已被证明可以增强病毒特异性CD8+ T细胞的细胞毒性以及直接的抗体类切换和B细胞的激活。因此，IL21+ CD4+ T细胞反应在病毒特异性免疫的配位中起着核心作用。令人惊讶的是，关于IL21+ 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+ T细胞反应在HIV-1 Elite控制器中存在鲁棒的HIV-1-特异性IL21+ T细胞反应，其优先靶向GAG蛋白内的表位。相反，在患有慢性HIV-1感染的受试者中，几乎没有IL21+ CD4+ T细胞反应。此外，我们有证据表明IL21信号可以将非控制的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IL21+ CD4+ T细胞反应可能是生成有效的CD8+ T细胞或基于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感染中早期抗逆转录病毒治疗是否保留了这些特定反应。 3.）评估HIV-1特异性IL21+ CD4+ T响应如何调节HIV-1特异性CD8+ T细胞，并增强其抑制病毒复制的能力。 4.）研究治疗性CD4靶向疫苗是否可以诱导这种反应，最后5。）评估IL21+ CD4+ T细胞如何调节HIV-1特异性B细胞功能。该提案的基本假设是HIV-1特异性IL21+ CD4+ T细胞通过调节HIV-1特异性B细胞功能并增加HIV-1特异性CD8+ T细胞的抑制活性，在控制病毒复制方面具有关键功能。预防或治疗疫苗中这些反应的诱导和传播对于长期寿命的有效病毒特异性免疫至关重要。 公共卫生相关性：迫切需要全球3,300万HIV-1感染的人。默克疫苗试验的最新失败以及由两种候选疫苗（ALVAC/AIDSVAX；“泰国试验”）组合组成的疫苗的意外临时成功表明，我们不太了解如何开发有效的疫苗。令人惊讶的是，使用的疫苗不仅诱导了抗体，还诱导了强大的HIV-1特异性CD4+ T细胞反应。来自小鼠模型的最新数据表明，分泌CD4+ T细胞反应的病毒特异性白介素21（IL21）对于支持病毒特异性CD8+ T细胞和B细胞免疫至关重要。因此，在该提案中，我们旨在定义HIV-1特异性IL21+ CD4+ T细胞反应在控制HIV-1感染中的作用，以确定这些反应的诱导是否应该是预防性和治疗性疫苗的关键组成部分。