Interleukin-21 Immune Mediated Control of HIV-1

描述（由申请人提供）：本提案描述了一个为期两年的指导培训计划，为申请人提供T细胞反应和HIV-1免疫发病机制领域的强化培训，从而提高申请人的研究技能和专业知识，以促进她作为独立研究者的发展。候选人将由资深研究人员Paul Goepfert博士和凯西韦弗博士指导，他们分别是HIV-1疫苗开发和免疫学领域公认的领导者。她还得到了多学科咨询委员会的支持，并将通过教学课程，会议和研讨会来实施教育计划。她将从事一个研究项目，研究IL-21 HIV-1特异性T细胞反应的作用，以及这些反应如何影响随后的CD 8 T淋巴细胞（CD 8-TL）反应的功能质量。尽管努力了解调节HIV-1遏制的免疫机制，但实现HIV-1持久控制所需的抗病毒CD 4+和CD 8 + T细胞应答的具体性质仍然在很大程度上未知。在大多数患者中，HIV-1特异性CD 8-TL逐渐变得功能低下，并持续处于疲惫状态，无法有效根除感染的目标。我们以前专注于响应的质量，并发现多功能的CD 8-TL，能够细胞因子分泌，增殖和脱粒在原发性感染中产生，并在HIV-1控制器中维持。然而，它仍然是不明确的因素是负责这些多功能的CD 8- TL的维护。一些证据表明，早期的CD 4 + T细胞介导的CD 8-TL引发事件可能是至关重要的编程有力的效应和记忆CD 8-TL的反应。慢性病毒感染的小鼠模型证明IL-21在抗病毒CD 8-TL应答的诱导、质量和寿命中的重要作用。我们的初步研究表明，HIV-1特异性CD 4 + T细胞在慢性感染期间产生IL-21的能力受到损害。有趣的是，我们证明了HIV-1特异性CD 8-TL也能够产生IL-21，并且与其CD 4 + T细胞对应物相比与病毒控制更好地相关。鉴于HIV-1中IL-21产生的改变及其在产生有效的病毒特异性效应CD 8-TL中的重要性，我们假设慢性HIV-1感染中多功能CD 8-TL的丧失是产生IL-21的HIV-1特异性CD 4+和CD 8 + T细胞功能废除的结果。利用多色流式细胞术，该项目提出了阐明后者的细胞在促进HIV-1控制者中产生保护性的、长寿命的HIV-1特异性CD 8-TL应答的定量和定性要求。了解CD 4 + T细胞辅助和CD 8 + T细胞功能质量与抗病毒疗效之间联系的分子机制将为重现有效的HIV-1疫苗提供新的见解。 公共卫生相关性：该提案旨在了解控制病毒的HIV-1感染患者的有效免疫反应。我们将研究如何加强这类反应。这些信息对于设计更好的治疗性和预防性HIV-1疫苗具有高度相关性。

DESCRIPTION (provided by applicant): This proposal describes a two-year mentored training program to provide the applicant with intensive training in the area of T cell responses and HIV-1 immunopathogenesis, thereby advancing the applicant's research skills and expertise to facilitate her development as an independent investigator. The candidate will be mentored by established investigators, Drs. Paul Goepfert and Casey Weaver, recognized leaders in the field of vaccine development for HIV-1 and immunology, respectively. She also has the support of a multidisciplinary advisory committee and will pursue a program of education through didactic coursework, conferences, and seminars. She will engage in a research project examining the role of IL-21 HIV-1-specific T cell responses and how these influence the functional quality of the ensuing CD8 T lymphocyte (CD8-TL) response. Despite efforts to understand the immune mechanisms that regulate containment of HIV-1, the specific qualities of anti-viral CD4+ and CD8+ T cell responses required to achieve durable control of HIV-1 remains largely unknown. In the majority of patients, HIV-1-specific CD8-TL gradually become less functional and persist in an exhausted state, unable to effectively eradicate infected targets. We have previously focused on the quality of the response and have found that polyfunctional CD8-TL, capable of cytokine secretion, proliferation, and degranulation are generated in primary infection and are maintained in HIV-1 controllers. However, it remains ill-defined which factors are responsible for the maintenance of these polyfunctional CD8- TL. Several lines of evidence suggest that the early CD4+ T cell-mediated CD8-TL priming events may be crucial for the programming of vigorous effector and memory CD8-TL responses. Mouse models of chronic viral infection demonstrate a vital role for IL-21, in the induction, quality, and longevity of anti-viral CD8-TL responses. Our preliminary studies demonstrate that HIV-1-specific CD4+ T cells are compromised in their ability to produce IL-21 during chronic infection. Interestingly, we demonstrate that HIV-1-specific CD8-TL are also capable of producing IL-21 and are even better associated with viral control than their CD4+ T cell counterparts. In light of the altered IL-21 production in HIV-1 and its proposed importance in the generation of effective virus-specific effector CD8-TL, we hypothesize that the loss of polyfunctional CD8-TL in chronic HIV-1 infection is a consequence of the functional abrogation of IL-21-producing HIV-1-specific CD4+ and CD8+ T cells. Utilizing polychromatic flow cytometry, this project proposes to elucidate the quantitative and qualitative requirements of the latter cells in contributing to the generation of protective, long-lived HIV-1-specific CD8-TL responses in HIV-1 controllers. Understanding the molecular mechanisms accounting for the link between CD4+ T cell help and CD8+ T cell functional quality and anti-viral efficacy will provide new insights for recapitulation into an effective HIV-1 vaccine. PUBLIC HEALTH RELEVANCE: This proposal aims to understand the effective immune responses in HIV-1 infected patients who control virus. We will study ways to enhance these types of responses. This information will be highly relevant for the design of better therapeutic and preventative HIV-1 vaccines.