Yang Xinyi, Zhao Xiaying, Zhu Yuqi, Shen Yinzhong, Wang Yanan, Lu Panpan, Jiang Zhengtao, Pan Hanyu, Yang Jinlong, Xun Jingna, Zhao Lin, Wang Jing, Liang Zhiming, Shen Xiaoting, Liang Yue, Lin Qinru, Liang Huitong, Jin Lu, Zhang Dengji, Liu Jun, Wang Bin, Jiang Shibo, Xu Jianqing, Wu Hao, Lu Hongzhou, Zhu Huanzhang
State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China.
Department of Infectious Disease, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, School of Basic Medical Sciences and Shanghai Public Health Clinical Centergrid.470110.3, Fudan University, Shanghai, China.
mBio. 2021 Aug 31;12(4):e0079521. doi: 10.1128/mBio.00795-21. Epub 2021 Jul 20.
Human immunodeficiency virus type 1 (HIV-1) cannot be completely eliminated because of existence of the latent HIV-1 reservoir. However, the facts of HIV-1 latency, including its establishment and maintenance, are incomplete. FKBP3, encoded by the gene, belongs to the immunophilin family of proteins and is involved in immunoregulation and such cellular processes as protein folding. In a previous study, we found that FKBP3 may be related to HIV-1 latency using CRISPR screening. In this study, we knocked out the gene in multiple latently infected cell lines to promote latent HIV-1 activation. We found that FKBP3 could indirectly bind to the HIV-1 long terminal repeat through interaction with YY1, thereby recruiting histone deacetylase 1/2 to it. This promotes histone deacetylation and induces HIV-1 latency. Finally, in a primary latent cell model, we confirmed the effect of knockout on the latent activation of HIV-1. Our results suggest a new mechanism for the epigenetic regulation of HIV-1 latency and a new potential target for activating latent HIV-1. The primary reason why AIDS cannot be completely cured is the existence of a latent HIV-1 reservoir. Currently, the facts of HIV-1 latency, including its establishment and maintenance, are incomplete. Using a CRISPR library in our earlier screening of genes related to HIV-1 latency, we identified as a candidate gene related to HIV-1 latency. Therefore, in this mechanistic study, we first confirmed the HIV-1 latency-promoting effect of FKBP3 and determined that FKBP3 promotes histone deacetylation by recruiting histone deacetylase 1/2 to the HIV-1 long terminal repeat. We also confirmed, for the first time, that FKBP3 can act as a transcription factor (TF) recruitment scaffold and participate in epigenetic regulation of HIV-1 latency. These findings suggest a new mechanism for the epigenetic regulation of HIV-1 latency and a new potential target for activating latent HIV-1.
由于潜伏性HIV-1储存库的存在，1型人类免疫缺陷病毒（HIV-1）无法被完全清除。然而，HIV-1潜伏的相关情况，包括其建立和维持，目前仍不明确。由该基因编码的FKBP3属于亲免素蛋白家族，参与免疫调节以及蛋白质折叠等细胞过程。在之前的一项研究中，我们通过CRISPR筛选发现FKBP3可能与HIV-1潜伏有关。在本研究中，我们在多个潜伏感染细胞系中敲除该基因以促进潜伏性HIV-1的激活。我们发现FKBP3可通过与YY1相互作用间接结合到HIV-1长末端重复序列上，从而招募组蛋白去乙酰化酶1/2至该序列。这促进了组蛋白去乙酰化并诱导HIV-1潜伏。最后，在原代潜伏细胞模型中，我们证实了该基因敲除对HIV-1潜伏激活的影响。我们的研究结果揭示了一种HIV-1潜伏表观遗传调控的新机制以及一个激活潜伏性HIV-1的新潜在靶点。艾滋病无法被完全治愈的主要原因是潜伏性HIV-1储存库的存在。目前，HIV-1潜伏的相关情况，包括其建立和维持，仍不明确。在我们早期使用CRISPR文库筛选与HIV-1潜伏相关基因的过程中，我们将该基因鉴定为与HIV-1潜伏相关的候选基因。因此，在这项机制研究中，我们首先证实了FKBP3具有促进HIV-1潜伏的作用，并确定FKBP3通过招募组蛋白去乙酰化酶1/2至HIV-1长末端重复序列来促进组蛋白去乙酰化。我们还首次证实FKBP3可作为转录因子（TF）招募支架并参与HIV-1潜伏的表观遗传调控。这些发现揭示了一种HIV-1潜伏表观遗传调控的新机制以及一个激活潜伏性HIV-1的新潜在靶点。
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