A novel compound that blocks HIV-1 replication inhibits the splicing regulatory function of SRSF10

Purpose: We have identified a new compound (1C8) that inhibits HIV-1 replication and that displays very low cellular toxicity. Here, we assess the molecular mechanisms of action of 1C8. Following transcription of the HIV-1 genome, its primary transcript is processed to produce dozens of distinct mRNAs through the alternative use of splice sites. Results: 1C8 decreases the activity of SRSF10, a cellular protein that controls the selection of splice sites in HIV-1 transcripts. 1C8 decreases the phosphorylation of SRSF10, and this change is associated with alterations in the interaction of SRSF10 with HIV-1 transcripts and factors that control splice site selection. Thus, 1C8 represents a novel compound with properties that are potentially useful for treating HIV-1 infection. Overall design: Examination of RNA-seq to investigate alternative splicing changes between control and 4 different concentrations of a drug that 1C8. 4 replicates were sequenced for each condition.

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Shkreta L, Blanchette M, Toutant J, Wilhelm E, Bell B, Story BA, Balachandran A, Cochrane A, Cheung PK, Harrigan PR, Grierson DS, Chabot B