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Antiviral and anti-inflammatory properties of novel anti-HIV candidate ABX464 promotes specifics RNA splicing while preserving cellular RNA integrity.

ABSTRACT: Antiviral and anti-inflammatory properties of novel anti-HIV candidate ABX464 promotes specifics RNA splicing while preserving cellular RNA integrity.

PROVIDER: PRJNA491672 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7869050_1.fastq.gz	Fastqsanger.gz
	SRR7869050_2.fastq.gz	Fastqsanger.gz
	SRR7869060_1.fastq.gz	Fastqsanger.gz
	SRR7869060_2.fastq.gz	Fastqsanger.gz
	SRR7869051_1.fastq.gz	Fastqsanger.gz

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Antiviral and anti-inflammatory properties of novel anti-HIV candidate ABX464 promotes specifics RNA splicing while preserving cellular RNA integrity.

Project description:Purpose: To ensure that ABX464 acted specifically on HIV splicing and did not significantly or globally affect the splicing events of human genes, we used an assembly approach of HIV (YU2 strain) putative transcripts and human long non-coding sequences from paired-reads (2x75bp) captured on a NimbleGen SeqCap® EZ Developer Library (Roche/NimbleGen). Methods: Cells were infected with 80 ng of p24/106 cells of the YU-2 strain for 4 to 6 hours and then rinsed with PBS before medium renewal, followed by high-throughput RNAseq from custom SeqCap EZ capture libraries. Each raw dataset of the samples contained between 5 and 30 million paired-end reads (75 bp), with an average of approximately 12 million raw reads per sample. Results: The raw reads were then cleaned and assembled per library to generate contigs, giving an average of 930 contigs per sample for further analyses. Conclusions: Our results show that high-throughput analyses coupled with bioinformatics-specific tools offers a comprehensive and more accurate view of mRNA splicing within a cell.

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Both anti-inflammatory and antiviral properties of novel drug candidate ABX464 are mediated by modulation of RNA splicing.

Project description:ABX464 is a first-in-class, clinical-stage, small molecule for oral administration that has shown strong anti-inflammatory effects in the DSS-model for inflammatory bowel disease (IBD) and also prevents replication of the HIV virus. ABX464 which binds to cap binding complex (CBC) has demonstrated safety and efficacy in a phase 2a proof-of-concept clinical trial in patients with Ulcerative colitis. Previously, with limited technologies, it was not possible to quantify the effect of ABX464 on viral and cellular RNA biogenesis. Here, using RNA CaptureSeq and deep sequencing, we report that ABX464 enhances the splicing of HIV RNA in infected PBMCs from six healthy individuals and also the expression and splicing of a single long noncoding RNA to generate the anti-inflammatory miR-124 both ex vivo and in HIV patients. While ABX464 has no effect on pre-mRNA splicing of cellular genes, depletion of CBC complex by RNAi leads to accumulation of intron retention transcripts. These results imply that ABX464 did not inhibit the function of CBC in splicing but rather strengthens it under pathological condition like inflammation and HIV infection. The specific dual ability of ABX464 to generate both anti-inflammatory miR-124 and spliced viral RNA may have applicability for the treatment of both inflammatory diseases and HIV infection.

| S-EPMC6349857 | biostudies-literature

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