FUNCTIONAL EVOLUTION OF SIV VARIANT VIRUSES

SIV 变种病毒的功能进化

• 批准号: 2057550
• 负责人: Mary L. Poss
• 金额: $ 7.1万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 1997-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2057550
• 关键词: HIV envelope protein gp120; Macaca; chimeric proteins; communicable disease transmission; genetic strain; lymph nodes; lymphocyte; monocyte; mucosa; nucleic acid sequence; polymerase chain reaction; protein structure function; receptor binding; simian immunodeficiency virus; virulence; virus envelope; virus infection mechanism

Genetic variation in the envelope gene and slow onset of clinical disease characterize lentivirus infections. Variants isolated late in infection are generally cytopathic in vitro and, in animal experiments, more pathogenic in vivo than the parent virus. Many defects in immune cell function are evident, however, during asymptomatic periods and may be essential factors in overall disease progression. At these early time points post-infection, virus is sequestered and replicating in lymph nodes but not in peripheral blood lymphocytes. Lymph nodes may, therefore, harbor a population of variant viruses functionally significant to viral pathogenesis. In this proposal, variants from lymph nodes and peripheral blood lymphocytes of preclinical SIVMne infected macaques will be analyzed and the functional properties conferred on gp120 by env mutations of these variants determined. Identification of early variant viruses with specific functional capabilities will be valuable in designing therapeutic intervention for early seroconverters. The specific aims are as follows: AIM 1: To determine the temporal relationship between SIV variants arising in lymph node to those found in PBMC of macaques infected with a molecular clone of SIVMne. DNA from lymph node and peripheral blood lymphocytes of SIV- infected macaques will be analyzed by PCR cloning of env. AIM 2: To construct chimeric viruses containing representative early variant gp120. Variant env sequences that are specific to lymph node or peripheral blood lymphocytes or that arise early in infection will be used to construct variant env-SIVMne chimeras. AIM 3: To determine the effect of env mutations on functional activity of gp120. Env-specific chimeras will be evaluated for the functional properties of receptor binding, cell activation and cell protein co-localization.

信封基因的遗传变异和临床疾病的缓慢发作 表征慢病毒感染。 感染后期隔离的变体 通常是体外细胞病变，在动物实验中，更多 与母体病毒相比，体内致病性。 免疫细胞中的许多缺陷 但是，在无症状的期间，功能是显而易见的，可能是 总体疾病进展的基本因素。 在这些早期 感染后点，病毒被隔离并在淋巴结中复制 但不在外周血淋巴细胞中。 因此，淋巴结可能 藏有变体病毒在功能上对病毒意义的人群 发病。 在此提案中，来自淋巴结和周围的变体 将分析临床前SIVMNE感染猕猴的血液淋巴细胞 这些功能特性由这些突变赋予GP120 确定的变体。 鉴定早期变体病毒 特定的功能功能对于设计治疗将很有价值 对早期血清发电机的干预。 具体目的如下： 目标1：确定SIV变体之间的时间关系 淋巴结中引起的猕猴的PBMC淋巴结 带有sivmne的分子克隆。 SIV-的淋巴结和外周血淋巴细胞的DNA Env的PCR克隆将分析感染的猕猴。 目标2：早期构建含有代表性的嵌合病毒 变体GP120。 特定于淋巴结或特定的变体环境序列 外周血淋巴细胞或感染早期出现的 用于构建变体环境嵌合体。 目标3：确定环境突变对功能活动的影响 GP120。 将评估ENV特定的嵌合体的功能 受体结合，细胞活化和细胞蛋白的特性 共定位。