Pathogenic mechanisms of HIV, viral reservoirs and sanct

该项目的目的是在细胞和分子水平上表征导致艾滋病发病的病毒-细胞相互作用；确定导致持续病毒感染的重要病毒库和庇护所；确定艾滋病毒与先天免疫系统细胞的相互作用；以及研究艾滋病先天免疫缺陷的机制。 识别所有持续感染艾滋病毒的细胞类型对于了解艾滋病的发病机制和开发更好的治疗方案具有深远的意义。我们已经在健康捐赠者中发现了CD56+CD3-自然杀伤(NK)细胞的一个亚群，这些细胞表达CD4以及HIV辅助受体CCR5和CXCR4。这些细胞在HIV感染者的外周血液中扩增，并能以依赖于CD4的方式被CCR5和CXCR4限制性的HIV-1分子克隆生产性感染。对HIV感染者样本的分析表明，纯化的NK细胞中存在病毒DNA，体外培养后病毒可以从这些细胞中解救出来。因此，这些细胞是体内永久病毒库的一部分。为了控制病毒复制和艾滋病的发展，需要解决病毒在这些细胞中的传播问题。我们已经产生了证据，表明在这些细胞中对病毒产生的调控存在几个不同。HIV对这些重要的先天免疫细胞的直接感染可能与艾滋病患者先天免疫缺陷有关。 细胞因子在HIV在原代细胞和组织中繁殖中的作用得到了进一步的研究。HIV的协同受体调节和细胞内机制是病毒传播的重要控制因素。细胞因子对HIV辅受体表达的调节是细胞类型特异性的。

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.