title: SRSF1 RNA Recognition Motifs Are Strong Inhibitors of HIV-1 Replication.
abstract: Replication of the integrated HIV-1 genome is tightly regulated by a series of cellular factors. In previous work we showed that transactivation of the HIV-1 promoter is regulated by the cellular splicing factor SRSF1. Here we report that SRSF1 can downregulate the replication of B, C, and D subtype viruses by >200-fold in a cell culture system. We show that viral transcription and splicing are inhibited by SRSF1 expression. Furthermore, SRSF1 deletion mutants containing the protein RNA-binding domains but not the arginine serine-rich activator domain can downregulate viral replication by >2,000-fold with minimal impact on cell viability and apoptosis. These data suggest a therapeutic potential for SRSF1 and its RNA-binding domains.
  
  
  OBJECTIVE
  Most drugs utilized to treat the HIV-1 infection are based on compounds that directly target proteins encoded by the virus. However, given the high viral mutation rate, the appearance of novel drug-resistant viral strains is common. Thus, there is a need for novel therapeutics with diverse mechanisms of action. In this study, we show that the cellular protein SRSF1 is a strong inhibitor of viral replication. Furthermore, expression of the SRSF1 RNA-binding domains alone can inhibit viral replication by >2,000-fold in multiple viral strains without impacting cell viability. Given the strong antiviral properties of this protein, the RNA-binding domains, and the minimal effects observed on cell metabolism, further studies are warranted to assess the therapeutic potential of peptides derived from these sequences.
authors: Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, Florida, USA.
authors: Sean
authors: S
authors: Paz
authors: Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, Florida, USA.
authors: Michael L
authors: ML
authors: Lu
authors: Vaccine Gene Therapy Institute Florida, Port Saint Lucie, Florida, USA.
authors: Hiroshi
authors: H
authors: Takata
authors: Vaccine Gene Therapy Institute Florida, Port Saint Lucie, Florida, USA.
authors: Lydie
authors: L
authors: Trautmann
authors: Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, Florida, USA mcaputi@fau.edu.
authors: Massimo
authors: M
authors: Caputi
mesh_terms: D000998:Antiviral Agents / Q000378:metabolism; D002460:Cell Line; D004252:DNA Mutational Analysis; D015497:HIV-1 / Q000276:immunology* / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D012326:RNA Splicing; D012367:RNA, Viral / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D000068103:Serine-Arginine Splicing Factors; D014158:Transcription, Genetic; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D009687:Nuclear Proteins; D012367:RNA, Viral; D016601:RNA-Binding Proteins; D000068103:Serine-Arginine Splicing Factors