HIV-1 Adaptation in the Central Nervous System

中枢神经系统中的 HIV-1 适应

• 批准号: 7643792
• 负责人: Joseph K Wong
• 金额: $ 35.48万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7643792
• 关键词: AIDS Dementia Complex; AIDS neuropathy; Affect; Algorithms; Anti-Retroviral Agents; Antibodies; Antibody Formation; Archives; Attention; Autologous; Autopsy; Binding; Biological Assay; Blood; Brain; Brain region; CCR5 gene; Cessation of life; Characteristics; Chronic; Clinical; Cognition Disorders; Cognitive; Colon; DNA; DNA Sequence; Dependence; Disease; Environment; Epitopes; Event; Evolution; Exhibits; Genetic; Genetic Polymorphism; Genotype; HIV; HIV Infections; HIV-1; Immune; Immunologics; In Situ; Individual; Infection; Length; Lung; Lymphoid; Lymphoid Tissue; Machine Learning; Mediating; Minor; Molecular Genetics; Motor; Neuraxis; Pathogenesis; Patients; Pattern; Peripheral Blood Lymphocyte; Phenotype; Plasma; Population; Positioning Attribute; Predisposition; Prevalence; RNA; RNA Sequences; Regression Analysis; Research; Resolution; Role; Sampling; San Francisco; Screening procedure; Sequence Analysis; Shapes; Site; Spleen; Staging; Syndrome; Time; Tissues; Tropism; Variant; Viral; Viral Genome; Virus; base; cohort; expression vector; genetic evolution; glycosylation; gp160; latent infection; lymph nodes; macrophage; monocyte; motor disorder; neuroadaptation; neurobehavioral; neuropathology; neurotoxicity; neutralizing antibody; novel; programs; prospective; receptor; receptor density; recombinant virus; relating to nervous system; viral RNA

DESCRIPTION (provided by applicant): HIV invasion of the central nervous system (CNS) occurs early after infection. Viral adaptation to replication in the CNS and its immunologic sequelae results in clinical neuropathological sequelae in up to 50% of untreated patients. Both host and viral determinants may mediate the neuropathology that results in the clinical syndromes of HIV associated dementia (HIV-D) and minor motor cognitive disorder (MMCD). In this study, we will examine the rate and possible determinants of evolution of HIV-1 in the CNS through 3 specific aims. SA 1: HIV-1 gp160 and nef sequence evolution will be assessed by comparing plasma and CSF virus in untreated patients identified in primary infection that are followed over 3 to 5 years employing rapid and sensitive screening of length polymorphism in V1-2 A/4-5 of env and clonal sequence analysis of env and nef. Concurrently, blood and CSF virus comparisons will be performed on longitudinal samples from a cohort of patients with chronic infection over a 3 to 5 year period to provide. Where differences are found, machine learning algorithms and multiple regression analysis will be performed to identify individual positions that contribute to sequence evolution with attention to glycosylation sites that alter neutralization by antibody, V3 positions that affect tropism or putative neurotoxicity, and CTL epitopes described in both env and nef. SA 2: In well characterized autopsy samples, CSF, plasma, parenchymal brain regions, spleen, lymph node and colon will be examined for proviral DNA sequences and RNA sequences, in order to characterize the composition of the HIV population in CNS and to determine the subset of viral variants that are productively replicating. SA 3: Prototypical env sequences identified in SA 1 and 2 will be cloned into expression vectors and co- receptor density dependence and usage and antibody neutralization susceptibility will be assessed. Sequence change in putative HLA restricted CTL epitopes in nef and env will be correlated with patient HLA type. Together, these studies will begin to identify and characterize immunologic determinants of HIV evolution in the CNS.

描述（由申请人提供）：中枢神经系统（CNS）的HIV入侵发生在感染后早期。在中枢神经系统中复制及其免疫后遗症的病毒适应导致多达50％的未治疗患者的临床神经病理后遗症。宿主和病毒决定因素均可介导导致HIV相关痴呆症（HIV-D）和次要运动认知障碍（MMCD）的临床综合症的神经病理学。在这项研究中，我们将通过3个特定目的检查中枢神经系统中HIV-1进化的速率和可能的决定因素。 SA 1：HIV-1 GP160和NEF序列演化将通过比较在原发性感染中鉴定出的未经处理的患者中的血浆和CSF病毒，这些患者经过3至5年的时间，使用ENV和NEF的V1-2 A/4-5的v1-2 A/4-5中的多态性筛查快速且敏感地筛选。同时，将对来自3到5年的慢性感染患者的纵向样本进行血液和CSF病毒比较。在发现差异的情况下，将进行机器学习算法和多重回归分析，以确定对序列进化的单个位置，以关注糖基化位点，这些位置会改变抗体，抗体，影响疗法或推测神经毒性的V3位置，以及在ENV和NEF中所描述的CTL表现。 SA 2：将检查尸检样品，CSF，血浆，实质大脑区域，脾脏，淋巴结和结肠，以进行病毒DNA序列和RNA序列，以表征CNS中HIV种群的组成并确定富有富有生产性的病毒变体的子集。 SA 3：在SA 1和2中鉴定出的原型ENV序列将被克隆到表达矢量中，并将评估使用和使用抗体中和敏感性。 NEF和ENV中假定的HLA限制CTL表位的序列变化将与患者HLA类型相关。总之，这些研究将开始识别和表征中枢神经系统中HIV进化的免疫决定因素。

项目成果

The Montreal Cognitive Assessment: A Pilot Study of a Brief Screening Tool for Mild and Moderate Cognitive Impairment in HIV-Positive Veterans.

• DOI: 10.1177/2325957414557270
• 发表时间: 2015-05-01
• 期刊: Journal of the International Association of Providers of AIDS Care
• 作者: Chartier, Maggie;Crouch, Pierre-Cedric;Wong, Joseph K
• 通讯作者: Wong, Joseph K