HIV-1 Adaptation in the Central Nervous System

中枢神经系统中的 HIV-1 适应

基本信息

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
项目类别：
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

项目摘要

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）：HIV 对中枢神经系统（CNS）的侵袭发生在感染后早期。病毒对中枢神经系统复制的适应及其免疫后遗症导致高达 50% 的未经治疗的患者出现临床神经病理学后遗症。宿主和病毒决定因素都可能介导导致 HIV 相关痴呆 (HIV-D) 和轻微运动认知障碍 (MMCD) 临床综合征的神经病理学。在这项研究中，我们将通过 3 个具体目标来研究中枢神经系统中 HIV-1 进化的速率和可能的决定因素。 SA 1：将通过比较原发感染中发现的未治疗患者的血浆和脑脊液病毒来评估 HIV-1 gp160 和 nef 序列进化，并采用快速灵敏的 V1-2 A/4 长度多态性筛查进行 3 至 5 年随访-5 的 env 以及 env 和 nef 的克隆序列分析。同时，还将对 3 至 5 年期间慢性感染患者队列的纵向样本进行血液和脑脊液病毒比较。如果发现差异，将进行机器学习算法和多元回归分析，以识别有助于序列进化的个体位置，并注意改变抗体中和的糖基化位点、影响向性或推定神经毒性的 V3 位置以及两者中描述的 CTL 表位环境和NEF。 SA 2：在充分表征的尸检样本中，将检查脑脊液、血浆、脑实质区域、脾脏、淋巴结和结肠的前病毒 DNA 序列和 RNA 序列，以表征中枢神经系统中 HIV 群体的组成并确定有效复制的病毒变体的子集。 SA 3：SA 1和2中鉴定的原型env序列将被克隆到表达载体中，并且将评估共受体密度依赖性和使用以及抗体中和敏感性。 nef 和 env 中推定的 HLA 限制性 CTL 表位的序列变化将与患者 HLA 类型相关。这些研究将共同开始识别和表征中枢神经系统中艾滋病毒进化的免疫决定因素。