Interferon-induced alteration of cellular factors affecting HIV alternative splicing, nuclear mRNA export and LTR transcription

干扰素诱导的细胞因子改变影响 HIV 选择性剪接、核 mRNA 输出和 LTR 转录

• 批准号: 429542362
• 负责人: Privatdozent Dr. Marek Widera
• 金额: --
• 依托单位: Institut für Medizinische Virologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/429542362?language=en
• 关键词: Interferon; induced; alteration; cellular; factors

The human immunodeficiency virus type 1 (HIV-1) has a relatively small genome, which is highly dispersed with cis-regulatory elements allowing a precise regulation of its gene products on the level of alternative pre-mRNA splicing. Since alternative splicing is processed by the cellular splicing machinery, cellular splicing regulatory proteins, which are heterogeneous nuclear ribonucleoproteins (hnRNP) and serine-arginine-rich splicing factors (SRSF), are crucial for viral replication. In addition, certain hnRNP proteins were shown to be involved in nuclear export of cellular HIV mRNAs. Furthermore, overexpression of SRSF1 or selected hnRNPs have been related to transcriptional inhibition of the HIV LTR-promoter. Type I Interferons (IFNs) play an important role in the innate immune defence against HIV-1 by inducing the transcription of IFN-stimulated genes (ISG) such as the restriction factor APOBEC3G establishing an anti-viral state in host cells. We could show that the expression levels of distinct hnRNP and SRSF coding mRNAs in T cells and macrophages are specifically repressed upon treatment with the clinically used IFNα subtype 2 and to an even higher extent with IFNα14, which is the most potent subtype against HIV-1. According to these unpublished findings, for the hnRNP family and SRSF proteins the term of IFN-repressed genes IRepGs seems to be more appropriate and describes a novel IFN-induced molecular mechanism affecting HIV-replication. Additionally, our precedent data demonstrate that in the interferon induced repression is abolished upon HIV-infection.We therefore assume that hnRNP and SRSF interacting with cis-regulatory elements in the HIV genome most likely significantly contribute to the anti-viral effect of IFNs against HIV. Thus, in this proposal we aim to investigate the impact of type I-III IFNs on the level of cellular and viral splicing, LTR transcription, and mRNA export, as well as its consequences for HIV-1 replication in cell lines and patient derived primary cells.

人类免疫缺陷病毒1型（HIV-1）具有相对小的基因组ECISE ECISE IS基因产物在水平的前MRNA剪接上。对于病毒复制，某些HNRNP蛋白与细胞HIV mRNA的核输出有关。刺激的基因（ISG），例如限制因子APOBEC3G。 srsf蛋白irepgs IREPG的术语似乎更合适，并描述了AFN诱导的分子机制，感染了HIV恢复原状。在HIV基因组中，最有可能显着有助于IFNS HIV的抗病毒作用。患者得出的原代细胞。