Pathogenic determinants of the SIV envelope transmembrane cytoplasmic domain

描述（由申请人提供）：关键的研究差距仍然存在于理解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;和3）保护个人免受艾滋病毒感染和/或疾病所需的免疫反应。非人灵长类动物（NHP）模型在开发人类HIV-1感染的范例和疫苗研究方面具有非常宝贵的价值，可以为人体试验提供信息。然而，仍然需要NHP模型，可以可靠和稳健地解决病毒/宿主决定因素和机制，宿主控制和保护免受感染。 在AI 074362的3年奖励期间，我们的实验室已经验证了一个强大的和新颖的NHP模型，以研究猪尾猕猴（PTM）中SIVmac的宿主控制，这是一种现在被认为对SIV诱导的疾病高度敏感的NHP物种。我们已经表明，当SIVmac 239，可重复地导致艾滋病的PTM，含有一个突变，消除了GYxxO运输信号在Env TM细胞质尾，所产生的病毒，称为？戈伊复制到与SIVmac 239相当的高急性RNA峰，但随着宿主免疫应答的开始被抑制到不可检测的水平。这些动物仅表现出肠道淋巴组织中CD 4/CCR 5 T细胞的轻度和短暂减少，并维持外周CD 4 T细胞的正常数量数月至数年。重要的是，？GY感染的PTM已受到保护，从同源SIVmac 239的挑战，并能够控制静脉感染的致病性异源SIV（E660），这表明免疫反应，可以控制？戈伊对遗传多样性致病性SIV也有效。试管婴儿？戈伊病毒粒子含有较少的Env，并且变得高度中和敏感，表明可以探索这种新的体内表型的细胞水平的基本机制。 提出了四个目标，以进一步扩展该模型的发展：目标#1将评估主机的决定因素，需要这种精英控制？GY感染的PTM;目标#2将定义宿主免疫反应？与保护和/或控制SIVmac 239和致病性异源SIV的挑战有关的GY感染的控制器;目标#3将开发独特的能力？戈伊模型进行全面评估的病毒学，结构，遗传和生物化学的变化，在Env的诱导下，探索潜在的机制？戈伊突变;目标#4将延长？宿主对致病性SHIV的控制和保护的戈伊模型，其中保护和控制的免疫相关性可以在HIV-1 Env.与其他NHP/SIV型号相比，此PTM/？戈伊模型提供了一个独特的机会，将病毒/细胞界面的事件与发病机制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性。

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.