SRSF1 acts as an IFN-I-regulated cellular dependency factor decisively affecting HIV-1 post-integration steps

• DOI: 10.3389/fimmu.2022.935800
• Publication Date: 2022-11-15T08:58:18Z
• Authors: Helene Sertznig; Fabian Roesmann; Alexander Wilhelm; Delia Heininger; Barbara Bleekmann; Carina Elsner; Mario Santiago; Jonas Schuhenn; Zehra Karakoese; Yvonne Benatzy; Ryan Snodgrass; Stefan Esser; Kathrin Sutter; Ulf Dittmer; Marek Widera
• Keywords: 0301 basic medicine; 570; repressed genes; Mononuclear; Messenger; Immunology; Medizin; 610; Antibodies; ASF; ISG; alternative splicing; 03 medical and health sciences; ISG (interferon stimulated genes); HIV Seropositivity; Genetics; Leukocytes; 2.1 Biological and endogenous factors; Humans; SF2/ASF; RNA, Messenger; Aetiology; Biomedical and Clinical Sciences; Serine-Arginine Splicing Factors; interferon; RC581-607; SRSF1; Infectious Diseases; SF2; Medical Microbiology; Biochemistry and cell biology; Interferon Type I; HIV-1; Leukocytes, Mononuclear; HIV/AIDS; RNA; Immunologic diseases. Allergy; Infection; transcription; Biotechnology

Efficient HIV-1 replication depends on balanced levels of host cell components including cellular splicing factors as the family serine/arginine-rich (SRSF, 1-10). Type I interferons (IFN-I) play a crucial role in innate immunity against by inducing expression IFN-stimulated genes (ISGs) potent restriction factors. The less well known IFN-repressed (IRepGs) might additionally affect viral downregulating dependency that are essential for life cycle; however, so far, knowledge about IRepGs involved infection is very limited. In this work, we could demonstrate and associated ISG induction correlated with low SRSF1 intestinal lamina propria mononuclear cells (LPMCs) peripheral blood (PBMCs) during acute chronic infection. HIV-1-susceptible lines primary monocyte-derived macrophages (MDMs), were transiently repressed upon treatment specific IFNα subtypes vitro. Mechanically, 4sU labeling newly transcribed mRNAs revealed IFN-mediated repression regulated early RNA level. knockdown led to an increase total levels, but relative proportion infectivity factor (Vif) coding transcripts, which counteract APOBEC3G-mediated restriction, was significantly reduced. presence high APOBEC3G increased LTR activity facilitated overall replication, despite decreased vif mRNA levels. contrast, overexpression impaired post-integration steps transcription, alternative splice site usage, virus particle production. Since efficient our data highlight far undescribed acting IFN-modulated decisively regulating steps.