HIV-1 Env conformation and tropism in brain colonization and neuroAIDS

HIV-1 Env 构象和向性在大脑定植和神经艾滋病中的作用

• 批准号: 9302568
• 负责人: PAUL R CLAPHAM
• 金额: $ 41.88万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9302568
• 关键词: AIDS Dementia Complex; Acquired Immunodeficiency Syndrome; Affect; Affinity; Binding; Biological Assay; Brain; DNA; Data; Dementia; Detection; Development; Disease; Evolution; HIV; HIV Envelope Protein gp120; HIV-1; Immune; Improve Access; Infection; Investigation; Knowledge; Measures; Mediating; Messenger RNA; Minor; Molecular Conformation; Neurocognitive; Neurologic; Neurons; Neurotropism; Patients; Population; Property; Proviruses; Risk; Structure; T-Lymphocyte; Time; Tissues; Tropism; V3 Loop; Variant; Virus; Virus Replication; brain tissue; design; insight; macrophage; nervous system disorder; neuroAIDS; neurotoxicity; neurotropic; neurovirulence; receptor

Highly mac-tropic HIV-1 R5 Envs that efficiently bind CD4 are associated with HIV neurological disease including HIV associated dementia (HAD). However, our knowledge of the properties and determinants of Envs that colonize brain and evolve into highly mac-tropic, neurovirulent variants are incomplete. Without this, we will not fully understand how and where neurotropic HIV-1 strains arise and develop into neurovirulent forms. Our preliminary data shows that R5 Envs derived from brain tissue of subjects without or with only minor neurocognitive disease (N/MCs) were mainly non-mac-tropic compared to those in HAD brain. This data suggests that mac-tropism is not required for HIV to enter brain tissue and opens up the possibility that HIV is carried in by infected T-cells, before mac-tropic and neurovirulent variants evolve. Env determinants that confer mac-tropism in HAD include residues within or proximal to the CD4bs. However, a single universal Env determinant of mac-tropism has not been identified and residues in different parts of gp120 e.g. the V1V2 and V3 loops were shown to modulate mac-tropism. These residues presumably increase the affinity of the Env trimer for CD4 either (1) directly via changes in contact residues or (2) indirectly by improving access to CD4 or enhancing CD4-induced conformational changes. We recently established a trimeric Env: CD4 binding assay, which shows mac-tropic Env trimers from brain bind CD4 efficiently, while non-mac-tropic Envs don't. We will use this and other assays to investigate how Env conformation and function varies in immune and brain tissue of N/MC and HAD subjects. Our hypothesis is that HAD is determined by the evolution of Envs with a higher affinity for CD4, that (1) carry less tightly closed Env trimers with a more exposed CD4bs, (2) are more easily triggered by CD4 and (3) mediate efficient macrophage infection. We propose 3 aims: Aim 1: To analyze HIV-1 replication and tropism in immune and brain tissue of N/MC subjects. We will establish whether envs recovered from brain of N/MC subjects are derived from actively replicating virus and the extent they are mac-tropic. Aim 2: To establish how Env conformation, tropism, receptor interactions and neurotoxicity vary in N/MC and HAD subjects. We will investigate how Env trimer conformation and function vary between immune and brain tissue of N/MC and HAD subjects. Aim 3: To identify determinants in gp120 and gp41 that modulate mac-tropism and evaluate their impact on Env conformation and function. We will identify Env determinants and properties associated with (1) colonization and viral replication in brain tissue and (2) neurovirulence and neuroAIDS. We will provide new insights to help develop strategies to identify HIV+ subjects at risk of neuroAIDS and `cure' approaches to attack persistent HIV in the CNS.

高效结合CD 4的高嗜性HIV-1 R5 Env与HIV神经系统疾病相关 艾滋病相关痴呆症（HAD）然而，我们对Envs的性质和决定因素的了解 在大脑中定居并进化成高度嗜大性的神经毒性变体是不完整的。如果没有这个，我们 尚不能完全理解嗜神经性HIV-1毒株如何以及在何处产生并发展成神经毒性形式。 我们的初步数据显示，R5 Envs来源于不含或仅含受试者的脑组织 与HAD相比，轻度神经认知疾病（N/MCs）主要为非嗜性。 这一数据表明，嗜宏性并不是HIV进入脑组织所必需的， HIV是由受感染的T细胞携带的，在嗜性和神经毒性变体进化之前。Env决定簇 在HAD中赋予大向性的残基包括在CD 4 b内或接近CD 4 b的残基。然而，一个普遍的 还没有鉴定出嗜性的Env决定簇，gp 120不同部分的残基，例如V1 V2 和V3环被证明调节向大型化。这些残基可能增加了与蛋白质的亲和力。 CD 4的Env三聚体（1）直接通过接触残基的变化或（2）间接通过改善获得 CD 4或增强CD 4诱导的构象变化。我们最近建立了三聚体Env：CD 4结合 结果表明，脑巨嗜性Env三聚体能有效结合CD 4，而非巨嗜性Env不能。 我们将使用这种和其他测定来研究Env构象和功能如何在免疫和 N/MC和HAD对象的脑组织。我们的假设是HAD是由Envs的进化决定的 对CD 4具有更高的亲和力，（1）携带封闭性较低的Env三聚体，具有更多暴露的CD 4 b，（2） 更容易被CD 4触发和（3）介导有效的巨噬细胞感染。我们提出三个目标： 目的1：分析N/MC患者免疫和脑组织中HIV-1的复制和嗜性。我们将 确定从N/MC受试者脑中回收的Env是否来源于活跃复制的病毒， 它们是大热带的程度。 目的2：确定N/MC中Env构象、向性、受体相互作用和神经毒性的变化， 有科目。我们将研究Env三聚体的构象和功能如何在免疫和大脑之间变化 N/MC和HAD受试者的组织。 目的3：鉴定gp 120和gp 41中调节向大型化的决定因素，并评估它们对 Env构象和功能。我们将确定与（1）相关的Env决定因素和属性 在脑组织中的定殖和病毒复制和（2）神经毒力和神经AIDS。我们将提供新的 深入了解，帮助制定战略，以确定有神经艾滋病风险的艾滋病毒+受试者和“治愈”方法， 攻击中枢神经系统中持续存在的艾滋病毒。