Pathogenic mechanisms of HIV, viral reservoirs and sanct

HIV的致病机制、病毒储存库和圣地

• 批准号: 6763821
• 负责人: George N. Pavlakis
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6763821
• 关键词: AIDS; HIV infections; clinical research; cytokine receptors; disease /disorder model; disease reservoirs; embryonic stem cell; gene expression; genetic regulation; genetically modified animals; host organism interaction; human immunodeficiency virus 1; human tissue; immunopathology; laboratory mouse; natural killer cells; pathologic process; protein structure function; receptor expression; tissue /cell culture; viral rescue; virus genetics; virus infection mechanism; virus protein; virus replication

This project aims to characterize virus-cell interactions leading to AIDS pathogenesis at the cellular and molecular level; to identify important virus reservoirs and sanctuaries that result in persistent virus infection; to identify HIV interactions with cells of the innate immune system; and to study the mechanisms of innate immune defects in AIDS. Identification of all cell types persistently infected by HIV is of profound importance for the understanding of AIDS pathogenesis and for the development of better treatment regimens. We have identified a subset of CD56+CD3- natural killer (NK) cells in healthy donors that express CD4 and the HIV coreceptors CCR5 and CXCR4. These cells are expanded in the peripheral blood of HIV infected individuals and can be productively infected by both CCR5 and CXCR4-restricted molecular clones of HIV-1 in a CD4-dependent manner. Analysis of samples from HIV infected persons showed that viral DNA is present in purified NK cells and virus could be rescued from these cells after in vitro cultivation. Therefore, these cells are part of the permanent virus reservoir in vivo. To control virus replication and AIDS development, virus propagation in these cells needs to be addressed. We have generated evidence indicating several differences in the regulation of virus production in these cells. Direct infection of these important innate immune cells by HIV may be relevant for the defects in innate immunity observed in AIDS patients. The role of cytokines in HIV propagation in primary cells and tissues has been studied further. HIV coreceptor regulation and intracellular mechanisms are important controls for virus propagation. Cytokine regulation of HIV coreceptor expression is cell type specific.

该项目旨在表征病毒细胞相互作用，从而导致在细胞和分子水平上艾滋病发病机理。确定导致持续性病毒感染的重要病毒储层和保护区；确定与先天免疫系统细胞的艾滋病毒相互作用；并研究艾滋病先天免疫缺陷的机制。 持续感染HIV的所有细胞类型的鉴定对于理解AIDS发病机理和发展更好治疗方案至关重要。我们已经确定了表达CD4和HIV CORECEPTORS CCR5和CXCR4的健康供体中CD56+CD3-天然杀伤（NK）细胞的子集。这些细胞在HIV感染个体的外​​周血中膨胀，并且可以以CCR5和CXCR4限制的HIV-1的CCR5和CXCR4限制性分子克隆以CD4依赖性方式施加。对艾滋病毒感染者的样品的分析表明，纯化的NK细胞中存在病毒DNA，并且在体外培养后可以从这些细胞中救出病毒。因此，这些细胞是体内永久性病毒储量的一部分。为了控制病毒复制并有助于发育，需要解决这些细胞中的病毒传播。我们已经产生了证据，表明这些细胞中病毒产生的调节有几个差异。通过HIV直接感染这些重要的先天免疫细胞可能与AIDS患者观察到的先天免疫缺陷有关。 已经进一步研究了细胞因子在原代细胞和组织中HIV传播中的作用。 HIV共受体调节和细胞内机制是病毒传播的重要控制。 HIV共受体表达的细胞因子调节是细胞类型的特异性。