Interleukin-21 Immune Mediated Control of HIV-1

描述(由申请者提供)：本建议描述了一项为期两年的指导性培训计划，为申请者提供T细胞反应和HIV-1免疫病理方面的强化培训，从而提高申请者的研究技能和专业知识，促进其作为独立研究人员的发展。候选人将由知名研究人员保罗·戈普费特博士和凯西·韦弗博士指导，他们分别是艾滋病毒-1疫苗开发和免疫学领域公认的领导者。她还得到了一个多学科咨询委员会的支持，并将通过教学课程、会议和研讨会来追求教育计划。她将参与一个研究项目，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CD8 T淋巴细胞(CD8-TL)反应的功能质量。尽管人们努力了解控制HIV-1遏制的免疫机制，但实现对HIV-1的持久控制所需的抗病毒CD4+和CD8+T细胞反应的特异性仍在很大程度上尚不清楚。在大多数患者中，HIV-1特异性CD8-TL功能逐渐减弱，持续处于疲惫状态，无法有效根除感染靶点。我们以前一直关注应答的质量，并发现多功能CD8-TL，能够分泌细胞因子、增殖和脱颗粒，在初次感染时产生，并在HIV-1控制者中保持。然而，目前仍不清楚哪些因素对这些多功能CD8-TL的维持起作用。多条证据表明，早期的CD4+T细胞介导的CD8-TL启动事件可能对强大的效应器和记忆性CD8-TL反应的编程至关重要。慢性病毒感染的小鼠模型表明，IL-21在抗病毒CD8-TL反应的诱导、质量和寿命方面起着至关重要的作用。我们的初步研究表明，HIV-1特异性的CD4+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CD8-TL也能够产生IL-21，并且比它们的CD4+T细胞更能更好地与病毒控制相关。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分子CD8-TL中的重要性，我们假设在慢性HIV-1感染中多功能CD8-TL的丧失是产生IL-21的HIV-1特异性CD4+和CD8+T细胞功能丧失的结果。利用多色流式细胞术，本项目建议阐明后一种细胞在帮助在HIV-1控制器中产生保护性的、长寿的HIV-1特异性CD8-TL反应中的数量和质量要求。了解CD4+T细胞HELP与CD8+T细胞功能质量和抗病毒疗效之间的联系的分子机制将为重述有效的HIV-1疫苗提供新的见解。 公共卫生相关性：这项建议旨在了解控制病毒的HIV-1感染患者的有效免疫反应。我们会研究如何加强这些类型的回应。这些信息将与设计更好的治疗性和预防性艾滋病毒-1疫苗高度相关。

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.