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

项目摘要 在致病性HIV和SIV感染中，先天性和适应性免疫应答不能控制病毒复制， 再加上持续的免疫激活，导致CD 4 +/CCR 5 + T细胞的进行性耗竭和AIDS。 许多HIV和SIV疫苗也未能引起可以广泛预防或治疗的免疫应答。 控制感染。虽然可以对HIV和SIV进行免疫控制，但其决定因素尚不清楚， 用疫苗诱导这些反应的能力。因此，迫切需要确定和了解 免疫反应，可以广泛地预防或控制HIV/SIV感染，并引发这些反应， 疫苗。描述了一种模型，其中缺失高度保守的运输基序内的Gly和Tyr， SIVmac 239包膜（Env）胞质尾区产生病毒（CMV戈伊），其在猪尾猕猴（PTM）中 急性复制到野生型水平，但变得高度控制的细胞免疫反应， 缺乏中和抗体。值得注意的是，控制猪戈伊感染的动物能够预防或 用同源SIVmac 239、异源SIVsmE 660和SHIV-SF 162 P3 N控制不同的攻击， 这些都是PTM的高致病性。最近的研究表明，在罕见的哺乳戈伊动物中获得的突变， 进展为AIDS和在PTM中的病毒进化，PTM中的CD 8细胞在HIV戈伊感染之前耗尽，已经暗示了 感染细胞中Env的极化运输的丧失是Escherichia戈伊改变的发病机制的驱动因素。这些 研究结果表明，Env运输在促进病毒的细胞间传播方面起着关键的双重作用， 在组织和逃避CD 8细胞免疫应答中。由于这些事件是由病毒学和 免疫突触，我们假设这个基序在体内促进感染性是至关重要的， 调节病毒对细胞免疫攻击的易感性。研究结果表明，干扰戈伊模型 这种基序不仅可以改变发病机制，而且还可以使有效的和广泛的保护性免疫应答， 发生.这一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） 确定免疫相关性的控制和反应，在控制不同的戈伊， 挑战; 2）通过表征病毒学差异来提供对该模型的机制性理解 在EMP戈伊和SIVmac 239感染过程中， 在新型mRNA疫苗的背景下运输免疫原性;以及4）为了扩展 这种保守的运输基序在SIV到HIV-1 Env中的免疫调节作用。这些高度新颖的 这些观察定位于为SIV和HIV疫苗领域的保护性免疫提供新的见解。

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.