Pathogenic determinants of the SIV envelope transmembrane cytoplasmic domain

描述(由申请人提供)：在理解1)艾滋病毒感染和疾病之间的联系；2)病毒控制的宿主决定因素；以及3)需要什么样的免疫反应来保护个人免受艾滋病毒感染和/或疾病方面，仍然存在关键的研究空白。非人灵长类动物(NHP)模型在开发人类HIV-1感染范例和为人类试验提供信息的疫苗研究方面具有非常宝贵的价值。然而，仍然需要能够可靠和有力地解决病毒/宿主决定因素和机制的NHP模型，这些决定因素和机制是宿主控制和防止感染的基础。 在AI074362的三年获奖期间，我们的实验室验证了一个强大而新颖的NHP模型来研究SIVmac在猪尾猕猴(PTM)中的寄主控制，PtM是一种NHP物种，现在被认为对SIV诱导的疾病高度敏感。我们已经证明，当可在PTMS中复制导致艾滋病的SIVmac239包含一个突变，该突变消除了Env TM细胞质尾部的GYxxO运输信号时，所产生的病毒被称为？Gyr，复制到与SIVmac239相当的高急性RNA峰，但随着宿主免疫反应的开始被抑制到无法检测的水平。这些动物仅表现出肠道淋巴组织中的CD4/CCR5 T细胞轻微和短暂的减少，并在几个月到几年的时间里保持外周CD4T细胞的正常数量。重要的是，感染了Gy射线的PTM已经免受同源SIVmac239挑战的保护，并能够控制静脉注射。一种致病性异源SIV(E660)的感染表明，能够控制？GY的免疫反应也对遗传多样性的致病SIV有效。在体外？？Gy病毒粒子含有较少的Env，并变得对中和高度敏感，这表明在细胞水平上的基本机制是可以探索的，这是这种新的体内表型的基础。 为进一步扩展这一模型的发展，提出了四个目标：目标1将评估在γ射线感染的PTMS中这一精英控制所需的宿主决定因素；目标2将定义与保护和/或控制SIVmac239和致病的、异源的SIV的挑战相关的γ射线感染控制器中的宿主免疫反应；目标3将通过全面评估由γ射线突变引起的环境中的病毒学、结构、遗传和生化变化来发展γ射线模型探索潜在机制的独特能力；目的#4将宿主控制和保护的γ射线模型扩展到致病性SIV，其中保护和控制的免疫相关性可以在HIV-1环境中进行评估。与其他NHP/SIV模型相比，这种PTM/GY模型提供了一个独特的机会，可以将病毒/细胞界面上的事件与致病的关键决定因素联系起来，并确定与控制和保护相关的免疫相关因素。

DESCRIPTION (provided by applicant): Critical research gaps remain in understanding 1) the link between HIV infection and disease; 2) host determinants for viral control; and 3) what immune responses are needed to protect individuals from HIV infection and/or disease. Non-human primate (NHP) models have been invaluable in developing paradigms for HIV-1 infection in humans and vaccine research that can inform human trials. However, NHP models are still needed that can reliably and robustly address viral/host determinants and mechanisms that underlie host control and protection from infection. During the 3 year award of AI074362, our laboratory has validated a powerful and novel NHP model to study host control of SIVmac in pigtail macaques (PTMs), a NHP species now recognized as being highly susceptible to SIV-induced disease. We have shown that when SIVmac239, which reproducibly causes AIDS in PTMs, contains a mutation that ablates a GYxxO trafficking signal in the Env TM cytoplasmic tail, the resulting virus, termed ?GY, replicates to a high acute RNA peak comparable to that of SIVmac239, but with the onset of host immune responses is suppressed to undetectable levels. These animals exhibit only a mild and transient reduction in CD4/CCR5 T-cells in gut lymphoid tissue and maintain normal numbers of peripheral CD4 T-cells for months to years. Importantly, ?GY-infected PTMs have been protected from homologous SIVmac239 challenges and able to control an i.v. infection of a pathogenic heterologous SIV (E660) suggesting that immune responses that can control ?GY are also effective against genetically diverse, pathogenic SIVs. In vitro ?GY virions contain less Env and become highly neutralization sensitive indicating that basic mechanisms at the cellular level, which underlie this novel in vivo phenotype, can be explored. Four aims are proposed to further extend the development of this model: Aim #1 will evaluate host determinants that are required for this elite control in ?GY-infected PTMs; Aim #2 will define host immune responses in ?GY-infected controllers that are relevant to protection and/or control of challenges with SIVmac239 and pathogenic, heterologous SIVs; Aim #3 will develop the unique ability of the ?GY model to explore underlying mechanisms by performing a comprehensive assessment of virologic, structural, genetic, and biochemical alterations in Env that are induced by the ?GY mutation; Aim #4 will extend the ?GY model of host control and protection to a pathogenic SHIV, where immune correlates of protection and control can be assessed in the context of an HIV-1 Env. In contrast to other NHP/SIV models, this PTM/?GY model provides a unique opportunity to link events at the viral/cellular interface to critical determinants of pathogenesis and to identify immune correlates that are relevant to control and protection.