HIV-1 Clones with Attenuated Cytopathic Effects

细胞病变效应减弱的 HIV-1 克隆

• 批准号: 6744170
• 负责人: DAVID CAMERINI
• 金额: $ 22.73万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6744170
• 关键词: SCID mouse; T lymphocyte; attenuated microorganism; clinical research; human immunodeficiency virus 1; human tissue; macrophage; tissue /cell culture; virus cytopathogenic effect; virus genetics; virus protein; virus replication

DESCRIPTION (provided by applicant): HIV pathogenesis in infected individuals and cytopathic effects in tissue culture are tightly correlated with viral load and replication. We propose to study several unique HIV-1 clones with attenuated cytopathic effects (CPE) derived from long term non progressors with high viral load, which will allow us to separate the determinants of viral load and replication from the determinants of HIV-1 pathogenesis. Most HIV-1 isolates from long-term non-progressors (LTNP) are CCR5-tropic (R5) and replicate poorly in vivo and in tissue culture, in contrast, some LTNP paradoxically have moderate to high viral load (LTNP-HVL), equivalent to that seen in individuals who progress to AIDS. We hypothesize and have preliminary data which indicate, that some LTNP-HVL derived HIV-1 clones are equally replication competent but less cytopathic than HIV-1 clones from individuals who progress to AIDS. The studies proposed in this application will use these unique clones to define the genetic determinants and mechanisms of pathogenesis of all HIV-1 clones. These unique HIV-1 clones may allow us to separate determinants of viral pathogenesis from determinants of viral replication, which may impact the development of AIDS therapeutics and vaccines. We have the following specific aims: 1. Characterize the replication and cytopathic effects, of R5 HIV-1 isolates from LTNP-HVL in FTOC, tonsil histoculture and SCID-hu mice. We will further characterize two HIV-1 clones with attenuated CPE that we have started to study and will characterize at least two more of these unique and informative HIV-1 biological clones in FTOC and tonsil histoculture. The most attenuated HIV-1 clones will also be studied in SCID-hu mice. 2. Characterize the Env and Nef associated phenotypes of R5 HIV-1 isolates from LTNP-HVL in tissue culture. These phenotypes will be studied since they have been linked to pathogenesis of HIV-1 due to their variation between HIV-1 clones from progressors and non-progressors and from early to late stages of infection.

描述（由申请方提供）：感染个体中的HIV发病机制和组织培养中的细胞病变效应与病毒载量和复制密切相关。我们建议研究几个独特的HIV-1克隆与衰减的细胞病变效应（CPE）来自长期非进展者与高病毒载量，这将使我们能够分离的决定因素的病毒载量和复制的HIV-1发病机制的决定因素。大多数来自长期非进展者（LTNP）的HIV-1分离株是CCR 5嗜性的（R5），并且在体内和组织培养中复制较差，相反，一些LTNP矛盾地具有中等至高病毒载量（LTNP-HVL），相当于进展为AIDS的个体中所见的病毒载量。我们假设并有初步数据表明，一些LTNP-HVL衍生的HIV-1克隆具有相同的复制能力，但比进展为AIDS的个体的HIV-1克隆的细胞病变性更低。本申请中提出的研究将使用这些独特的克隆来定义所有HIV-1克隆的遗传决定因素和发病机制。这些独特的HIV-1克隆可能使我们能够将病毒发病机制的决定因素与病毒复制的决定因素分开，这可能会影响艾滋病治疗和疫苗的发展。我们有以下具体目标：1.在FTOC、扁桃体组织培养和SCID-hu小鼠中表征LTNP-HVL的R5 HIV-1分离株的复制和细胞病变效应。我们将进一步表征我们已经开始研究的两个具有减毒CPE的HIV-1克隆，并将在FTOC和扁桃体组织培养中表征至少两个以上这些独特且信息丰富的HIV-1生物克隆。最减毒的HIV-1克隆也将在SCID-hu小鼠中进行研究。2.在组织培养物中表征LTNP-HVL中R5 HIV-1分离株的Env和Nef相关表型。将研究这些表型，因为它们与HIV-1的发病机制有关，因为它们在来自进展者和非进展者的HIV-1克隆之间以及从感染的早期到晚期之间存在差异。