Johannes Cm Schlachetzki, Sara Gianella, Zhengyu Ouyang, Addison J Lana, Xiaoxu Yang, Sydney O'Brien, Jean F Challacombe, Peter J Gaskill, Kelly L Jordan-Sciutto, Antoine Chaillon, David Moore, Cristian L Achim, Ronald J Ellis, Davey M Smith, Christopher K Glass
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引用次数: 0
Abstract
The presence of HIV in sequestered reservoirs is a central impediment to a functional cure, allowing HIV to persist despite life-long antiretroviral therapy (ART), and driving a variety of comorbid conditions. Our understanding of the latent HIV reservoir in the central nervous system is incomplete, because of difficulties in accessing human central nervous system tissues. Microglia contribute to HIV reservoirs, but the molecular phenotype of HIV-infected microglia is poorly understood. We leveraged the unique "Last Gift" rapid autopsy program, in which people with HIV are closely followed until days or even hours before death. Microglial populations were heterogeneous regarding their gene expression profiles but showed similar chromatin accessibility landscapes. Despite ART, we detected occasional microglia containing cell-associated HIV RNA and HIV DNA integrated into open regions of the host's genome (∼0.005%). Microglia with detectable HIV RNA showed an inflammatory phenotype. These results demonstrate a distinct myeloid cell reservoir in the brains of people with HIV despite suppressive ART. Strategies for curing HIV and neurocognitive impairment will need to consider the myeloid compartment to be successful.
艾滋病病毒在潜伏库中的存在是功能性治愈的主要障碍,它使艾滋病病毒在终生抗逆转录病毒疗法(ART)的作用下依然存在,并导致多种并发症。由于难以获得人体中枢神经系统组织,我们对中枢神经系统中潜伏的艾滋病病毒库的了解并不全面。小胶质细胞是艾滋病病毒库的组成部分,但人们对感染艾滋病病毒的小胶质细胞的分子表型知之甚少。我们利用独特的 "最后的礼物 "快速尸检项目,对艾滋病病毒感染者进行密切跟踪,直到他们死亡前几天甚至几小时。小胶质细胞群的基因表达谱不尽相同,但染色质可及性景观相似。尽管进行了抗逆转录病毒疗法,我们仍偶尔检测到小胶质细胞含有细胞相关的 HIV RNA 和整合到宿主基因组开放区域的 HIV DNA(0.005%)。检测到 HIV RNA 的小胶质细胞表现出炎症表型。这些结果表明,尽管抗逆转录病毒疗法得到了抑制,但艾滋病毒感染者的大脑中仍存在一个独特的髓细胞储库。治疗艾滋病毒和神经认知障碍的策略需要考虑到髓系细胞区,这样才能取得成功。
期刊介绍:
Life Science Alliance is a global, open-access, editorially independent, and peer-reviewed journal launched by an alliance of EMBO Press, Rockefeller University Press, and Cold Spring Harbor Laboratory Press. Life Science Alliance is committed to rapid, fair, and transparent publication of valuable research from across all areas in the life sciences.