Tedbury Philip R, Mahboubi Darius, Puray-Chavez Maritza, Shah Raven, Ukah Obiaara B, Wahoski Claudia C, Fadel Hind J, Poeschla Eric M, Gao Xinlin, McFadden William M, Gaitanidou Maria, Kesesidis Nikolaos, Kirby Karen A, Vanderford Thomas H, Kvaratskhelia Mamuka, Achuthan Vasudevan, Behrens Ryan T, Engelman Alan N, Sarafianos Stefan G
Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine; Atlanta, GA, USA.
Children's Healthcare of Atlanta; Atlanta, GA, USA.
bioRxiv. 2024 Dec 6:2024.12.06.627169. doi: 10.1101/2024.12.06.627169.
Disruption of HIV-1 Integrase (IN) interactions with the host-factor Lens Epithelium-Derived Growth Factor (LEDGF)/p75 leads to decreased, random integration, increased latent infection, and described here, accumulation of HIV-1 antisense RNA (asRNA). asRNA increase was observed following interruptions of IN-LEDGF/p75 interactions either through pharmacologic perturbations of IN-LEDGF/p75 by treatment with allosteric HIV-1 integrase inhibitors (ALLINIs) or in cell lines with LEDGF genetic knockout. Additionally, by impairing Tat-dependent HIV transcription, asRNA abundance markedly increases. Illumina sequencing characterization of asRNA transcripts in primary T cells infected in the presence of ALLINIs showed that most initiate from within the HIV-1. Overall, loss of IN-LEDGF/p75 interactions increase asRNA abundance. Understanding the relationship between ALLINIs, integration sites, asRNA, and latency could aid in future therapeutic strategies.
HIV-1整合酶（IN）与宿主因子晶状体上皮衍生生长因子（LEDGF）/p75之间的相互作用被破坏会导致整合减少、随机整合、潜伏感染增加，并且如本文所述，会导致HIV-1反义RNA（asRNA）积累。在用变构HIV-1整合酶抑制剂（ALLINIs）处理对IN-LEDGF/p75进行药理学扰动后，或在LEDGF基因敲除的细胞系中，观察到IN-LEDGF/p75相互作用中断后asRNA增加。此外，通过损害Tat依赖性HIV转录，asRNA丰度显著增加。在ALLINIs存在的情况下感染的原代T细胞中asRNA转录本的Illumina测序表征表明，大多数asRNA转录本起始于HIV-1内部。总体而言，IN-LEDGF/p75相互作用的丧失会增加asRNA丰度。了解ALLINIs、整合位点、asRNA和潜伏之间的关系可能有助于未来的治疗策略。
