Role of SIV and HIV Env cytoplasmic tail in pathogenesis and protective immunity

SIV和HIV Env胞质尾在发病机制和保护性免疫中的作用

• 批准号: 10092084
• 负责人: James A Hoxie
• 金额: $ 76.19万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092084
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Anatomy; Animals; Antiviral Agents; Biological; Biological Assay; Blood; CCR5 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Line; Cells; Chronic; Code; Control Animal; Coupled; Cytoplasmic Tail; Data; Disease; Epitopes; Event; Evolution; Exhibits; Future; Gut associated lymphoid tissue; HIV; HIV vaccine; HIV-1; HIV/SIV vaccine; Image; Immune; Immune response; Immunity; Immunocompetence; Impairment; In Vitro; Infection; Infection Control; Intervention; Lead; Macaca nemestrina; Maps; Mediating; Modeling; Molecular Cloning; Mutation; Outcome; Pathogenesis; Pathogenicity; Plasma; Play; Positioning Attribute; Predisposition; RNA vaccine; Regenerative capacity; Role; SIV; SIV Vaccines; Signal Transduction; Sorting - Cell Movement; T cell response; T-Lymphocyte; Testing; Tissues; Vaccines; Viral; Viral Proteins; Virus; Virus Diseases; Virus Replication; adaptive immune response; cellular targeting; immune activation; immunogenicity; immunological synapse; immunoregulation; in vivo; insight; macrophage; monocyte; nef Protein; neutralizing antibody; nonhuman primate; novel; novel vaccines; prevent; response; simian human immunodeficiency virus; synaptogenesis; trafficking; viral RNA; viral transmission; virological synapse

Project Summary In pathogenic HIV and SIV infection innate and adaptive immune responses fail to control viral replication and, coupled with persisting immune activation, lead to the progressive depletion of CD4+/CCR5+ T cells and AIDS. Numerous HIV and SIV vaccines have also failed to elicit immune responses that can broadly prevent or control infection. Although immune control of HIV and SIV can occur, the determinants are unclear, as is the ability to induce these responses with vaccines. There is thus, an urgent need to identify and understand immune responses that can broadly prevent or control HIV/SIV infection and to elicit these responses with vaccines. A model is described in which deletion of a Gly and Tyr within a highly conserved trafficking motif in the SIVmac239 envelope (Env) cytoplasmic tail produces a virus (∆GY) that in pigtail macaques (PTM) replicates acutely to wildtype levels, but becomes highly controlled by cellular immune responses in the absence of neutralizing antibodies. Remarkably, animals that control ∆GY infection are able to prevent or control diverse challenges with homologous SIVmac239, heterologous SIVsmE660 and SHIV-SF162P3N, which are all highly pathogenic in PTM. Recent studies of mutations acquired in rare ∆GY animals that progressed to AIDS and of viral evolution in PTM depleted of CD8 cells prior to ∆GY infection, have implicated the loss of polarized trafficking of Env in infected cells as a driver for ∆GY's altered pathogenesis. These findings have suggested that Env trafficking plays a critical dual role in promoting both cell-cell spread of virus in tissues and in evading CD8 cellular immune responses. As these events are mediated by virologic and immunologic synapses, respectively, we hypothesize that this motif is critical in vivo in promoting infectivity and modulating viral susceptibility to cellular immune attack. Findings with the ∆GY model suggest that disrupting this motif can not only alter pathogenesis but also enable potent and broadly protective immune responses to occur. This testable hypothesis and its implications for vaccines will be assessed in 4 Aims: 1) To identify the immune correlates of ∆GY control and responses that are shared during control of diverse challenges; 2) To provide a mechanistic understanding of this model by characterizing differences in virologic and immunologic synapses during ∆GY and SIVmac239 infection; 3) To assess the impact of alterations in Env trafficking on immunogenicity in the context of a novel mRNA vaccine; and 4) To extend findings for the immunomodulatory role of this conserved trafficking motif in SIV to an HIV-1 Env. These highly novel observations are positioned to provide new insights into protective immunity for the SIV and HIV vaccine fields.

项目摘要 在致病性HIV和SIV感染中，先天性和适应性免疫治疗无法控制病毒复制，并且 再加上持续的免疫激活，导致CD4+/CCR5+ T细胞和AIDS的进行性耗竭。 许多艾滋病毒和SIV疫苗也未能引起可以广泛预防或 控制感染。尽管可以发生HIV和SIV的免疫控制，但确定剂尚不清楚， 用疫苗诱导这些反应的能力。因此，迫切需要识别和理解 可以广泛预防或控制HIV/SIV感染并引起这些反应的免疫反应 疫苗。描述了一个模型，其中在高度组成的贩运图案中删除了gly和tyr的模型 SIVMAC239 CYLEVELOPE（ENV）细胞质尾巴产生尾巴猕猴（PTM）的病毒（∆GY） 急性复制到野生型水平，但受到细胞免疫反应的高度控制 缺乏中和抗体。值得注意的是，控制∆GY感染的动物能够预防或 通过同源SIVMAC239，异源SIVSME660和SHIV-SF162P3N，控制潜水员的挑战， 在PTM中都是高致病性的。在稀有∆GY动物中获得的突变的最新研究 在ΔGY感染之前耗尽CD8细胞的PTM中的艾滋病和病毒进化已实施 ENV在受感染细胞中的极化运输的丧失是∆GY发病机理改变的驱动因素。这些 调查结果表明，ENV运输在促进病毒的两个细胞细胞扩散中起着至关重要的双重作用 在组织和逃避CD8细胞免疫反应中。由于这些事件是由病毒学和 免疫突触，我们假设该基序在促进感染和体内至关重要 调节病毒性对细胞免疫攻击的敏感性。 ΔGY模型的发现表明破坏 该基序不仅可以改变发病机理，而且可以使潜力和广泛保护的免疫复杂到达 发生。该可检验的假设及其对疫苗的影响将在4个目标中进行评估：1） 确定在潜水员控制过程中共享∆GY控制和反应的免疫相关性 挑战； 2）通过表征病毒学的差异来提供对该模型的机械理解 以及∆GY和SIVMAC239感染期间的免疫突触； 3）评估ENV改变的影响 在新型mRNA疫苗的背景下，贩运免疫原性； 4）扩展了 该构成在SIV中的贩运图案的免疫调节作用是HIV-1 Env。这些高度新颖 观察结果可以为SIV和HIV疫苗场提供有关保护性免疫的新见解。