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: 9203076
• 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/9203076
• 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; Staging; 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.

高度Mac-Tropic HIV-1 R5 ENV认为有效结合CD4与HIV神经疾病有关 包括艾滋病毒相关痴呆症（HAT）。但是，我们对ENV的属性和决定因素的了解 将大脑殖民并演变成高度Mac的神经毒力变体是不完整的。没有这个，我们 将无法完全了解神经性HIV-1菌株的出现以及在何处形成神经毒动形式。 我们的初步数据表明，R5 Envs来自没有或仅具有的受试者的脑组织 与脑中的神经认知疾病（N/MC）相比，次要神经认知疾病（N/MC）主要是非MAC-热带疾病。 该数据表明，艾滋病毒不需要麦克风热量进入脑组织并打开了可能性 在MAC-热带和神经毒势变体发展之前，该艾滋病毒是由感染的T细胞携带的。 env决定因素 这种赋予的Mac-Horpism在CD4B中包括或近端包括残留物。但是，一个通用 ENV尚未鉴定出MAC-热 - 热态的决定因素，并且在GP120的不同部分中的残基，例如V1V2 证明V3环路可调节MAC-热爱。这些残基大概增加了 CD4的Env Trimer（1）通过接触残基的更改或（2）间接地通过提高访问权限而直接 CD4或增强CD4诱导的构象变化。我们最近建立了三聚合物env：CD4结合 分析有效地显示了来自脑的Mac-Tropic Env Trimers，而非MAC-Tropic Envs则没有。 我们将使用此和其他测定法来研究ENV构象和功能如何在免疫和 N/MC的脑组织，并具有受试者。我们的假设是通过Envs的演变决定了 对CD4的亲和力较高，（1）携带较少的紧密封闭的Env Trimers具有更裸露的CD4BS，（2）为（2） 更容易由CD4触发，（3）介导有效的巨噬细胞感染。我们提出了3个目标： 目的1：分析N/MC受试者的免疫和脑组织中的HIV-1复制和向热学。我们将 确定是否从N/MC受试者的大脑中恢复过的ENV是从主动复制病毒和 它们是MAC热带的程度。 目的2：建立ENV构象，向流，受体相互作用和神经毒性如何在N/MC和 有主题。我们将研究Env Trimer构象和功能如何在免疫和大脑之间变化 N/MC的组织，有受试者。 目标3：确定在GP120和GP41中调节MAC-热疗法的决定因素并评估其对其对 env构象和功能。我们将确定与（1）相关的ENV决定因素和属性 脑组织中的定植和病毒复制以及（2）神经动力和神经辅助。我们将提供新的 见解以帮助制定策略来识别有神经辅助和“治愈”方法风险的艾滋病毒+受试者 中枢神经系统攻击持续的艾滋病毒。