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LEDGIN介导的整合酶与LEDGF/p75相互作用的抑制可减少残留潜伏HIV的激活。

LEDGIN-mediated Inhibition of Integrase-LEDGF/p75 Interaction Reduces Reactivation of Residual Latent HIV.

作者信息

Vranckx Lenard S, Demeulemeester Jonas, Saleh Suha, Boll Annegret, Vansant Gerlinde, Schrijvers Rik, Weydert Caroline, Battivelli Emilie, Verdin Eric, Cereseto Anna, Christ Frauke, Gijsbers Rik, Debyser Zeger

机构信息

Laboratory of Molecular Virology and Gene Therapy, Department of Pharmacological and Pharmaceutical Sciences, KU Leuven, Kapucijnenvoer 33 VTCB +5, 3000 Leuven, Flanders, Belgium.

Laboratory of Molecular Virology, Centre for Integrative Biology (CIBIO), University of Trento, Via delle Regole 101, 38123 Trento, Italy.

出版信息

EBioMedicine. 2016 Jun;8:248-264. doi: 10.1016/j.ebiom.2016.04.039. Epub 2016 May 13.

DOI:10.1016/j.ebiom.2016.04.039
PMID:27428435
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4919729/
Abstract

Persistence of latent, replication-competent Human Immunodeficiency Virus type 1 (HIV-1) provirus is the main impediment towards a cure for HIV/AIDS (Acquired Immune Deficiency Syndrome). Therefore, different therapeutic strategies to eliminate the viral reservoirs are currently being explored. We here propose a novel strategy to reduce the replicating HIV reservoir during primary HIV infection by means of drug-induced retargeting of HIV integration. A novel class of integration inhibitors, referred to as LEDGINs, inhibit the interaction between HIV integrase and the LEDGF/p75 host cofactor, the main determinant of lentiviral integration site selection. We show for the first time that LEDGF/p75 depletion hampers HIV-1 reactivation in cell culture. Next we demonstrate that LEDGINs relocate and retarget HIV integration resulting in a HIV reservoir that is refractory to reactivation by different latency-reversing agents. Taken together, these results support the potential of integrase inhibitors that modulate integration site targeting to reduce the likeliness of viral rebound.

摘要

潜伏的、具有复制能力的1型人类免疫缺陷病毒（HIV-1）前病毒的持续存在是治愈HIV/AIDS（获得性免疫缺陷综合征）的主要障碍。因此，目前正在探索不同的治疗策略来消除病毒储存库。我们在此提出一种新策略，即在原发性HIV感染期间，通过药物诱导的HIV整合重新靶向，减少正在复制的HIV储存库。一类新型的整合抑制剂，称为LEDGINs，可抑制HIV整合酶与LEDGF/p75宿主辅因子之间的相互作用，LEDGF/p75是慢病毒整合位点选择的主要决定因素。我们首次表明，LEDGF/p75的缺失会阻碍细胞培养中HIV-1的重新激活。接下来，我们证明LEDGINs可重新定位并重新靶向HIV整合，从而产生一个对不同潜伏逆转剂的重新激活具有抗性的HIV储存库。综上所述，这些结果支持了整合酶抑制剂调节整合位点靶向以降低病毒反弹可能性的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ece/4919729/a4588a640a46/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ece/4919729/7ced8dd006ca/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ece/4919729/5c7235e0078d/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ece/4919729/53427840b8e2/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ece/4919729/fec95790c017/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ece/4919729/3c7bce1f6dc7/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ece/4919729/46ad3703c4b7/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ece/4919729/a4588a640a46/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ece/4919729/7ced8dd006ca/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ece/4919729/5c7235e0078d/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ece/4919729/53427840b8e2/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ece/4919729/fec95790c017/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ece/4919729/3c7bce1f6dc7/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ece/4919729/46ad3703c4b7/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ece/4919729/a4588a640a46/gr7.jpg

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