Pathogenic mechanisms of HIV, viral reservoirs and sanct

该项目的目的是在细胞和分子水平上确定导致艾滋病发病的病毒-细胞相互作用的特征;确定导致持续病毒感染的重要病毒库和避难所;确定艾滋病毒与先天免疫系统细胞的相互作用;并研究艾滋病先天免疫缺陷的机制。 鉴定HIV持续感染的所有细胞类型对于理解AIDS发病机制和开发更好的治疗方案具有深远的重要意义。我们已经在健康供体中鉴定了一个表达CD 4和HIV辅助受体CCR 5和CXCR 4的CD 56 + CD 3-自然杀伤（NK）细胞亚群。这些细胞在HIV感染个体的外周血中扩增，并且可以以CD 4依赖性方式被HIV-1的CCR 5和CXCR 4限制性分子克隆有效感染。对HIV感染者样本的分析表明，病毒DNA存在于纯化的NK细胞中，体外培养后可从这些细胞中拯救病毒。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AIDS发展，需要解决这些细胞中的病毒繁殖。我们已经产生的证据表明，在这些细胞中的病毒生产的调节的几个差异。这些重要的先天免疫细胞被HIV直接感染可能与在AIDS患者中观察到的先天免疫缺陷有关。 细胞因子在HIV在原代细胞和组织中的传播中的作用已经被进一步研究。HIV辅助受体调节和细胞内机制是病毒繁殖的重要控制因素。细胞因子对HIV辅助受体表达的调节具有细胞类型特异性。

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.