HIV integration in the human brain is linked to microglial activation and 3D genome remodeling.
HIV integration in the human brain is linked to microglial activation and 3D genome remodeling.
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DOI：
10.1016/j.molcel.2022.11.016
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发表时间：
2022-12
期刊：
影响因子：
16
通讯作者：
A. Plaza-Jennings;A. Valada;Callan O’Shea;Marina Iskhakova;Benxia Hu;B. Javidfar;Gabriella Ben Hutta;Tova Y Lambert;Jacinta Murray;Bibi S. Kassim;Sandhya Chandrasekaran;Benjamin K. Chen;Susan Morgello;Hyejung Won;S. Akbarian
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作者：
A. Plaza-Jennings;A. Valada;Callan O’Shea;Marina Iskhakova;Benxia Hu;B. Javidfar;Gabriella Ben Hutta;Tova Y Lambert;Jacinta Murray;Bibi S. Kassim;Sandhya Chandrasekaran;Benjamin K. Chen;Susan Morgello;Hyejung Won;S. Akbarian
为了探索HIV感染大脑中的基因组组织和功能，我们将单核转录组学，细胞类型特异性染色体构象映射和病毒整合位点测序（IS-seq）应用于患有脑炎（HIVE）和没有（HIV+）的个体的额叶皮质。HIVE小胶质细胞中3D基因组区室结构的去抑制变化与干扰素（IFN）信号传导和细胞迁移途径的转录激活有关，而HIVE和HIV+小胶质细胞中均发生了神经元健康和信号传导基因的转录下调和抑制性区室化。IS-seq回收了1，221个脑整合位点，与外周淋巴细胞相比显示出不同的基因组模式，并富集了感染后新动员到容许染色质环境中的序列。病毒转录发生在高度活化的小胶质细胞亚群中，占HIVE脑中所有细胞核的0.33%。我们的研究结果指出了HIV中小胶质细胞-神经元相互作用的破坏，并将逆转录病毒整合与感染期间小胶质细胞3D基因组的重塑联系起来。
To explore genome organization and function in the HIV-infected brain, we applied single-nuclei transcriptomics, cell-type-specific chromosomal conformation mapping, and viral integration site sequencing (IS-seq) to frontal cortex from individuals with encephalitis (HIVE) and without (HIV+). Derepressive changes in 3D genomic compartment structures in HIVE microglia were linked to the transcriptional activation of interferon (IFN) signaling and cell migratory pathways, while transcriptional downregulation and repressive compartmentalization of neuronal health and signaling genes occurred in both HIVE and HIV+ microglia. IS-seq recovered 1,221 brain integration sites showing distinct genomic patterns compared with peripheral lymphocytes, with enrichment for sequences newly mobilized into a permissive chromatin environment after infection. Viral transcription occurred in a subset of highly activated microglia comprising 0.33% of all nuclei in HIVE brain. Our findings point to disrupted microglia-neuronal interactions in HIV and link retroviral integration to remodeling of the microglial 3D genome during infection.