Abstract
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.
Highlights
ABX464 is a novel drug candidate for treating patients infected with human immunodeficiency virus (HIV) and patients with ulcerative colitis (ABIVAX, data in file)
ABX464 is a small molecule that binds to the cap binding complex (CBC)[2], a complex at the 5′-end of the pre-mRNA transcript that promotes the initial interaction with transcription and processing machinery[3,4,5]
Successful infection and production of new infectious HIV particles requires the balanced expression of seven viral proteins (Rev, Tat, Nef, Vif, Vpr, Vpu and Env) that are produced by splicing of the HIV-1 primary 9 kilobases transcript; among these, the Tat and Rev factors are essential for viral gene expression at the transcriptional and posttranscriptional levels in infected cells[18,19]
Summary
ABX464 is a novel drug candidate for treating patients infected with human immunodeficiency virus (HIV) and patients with ulcerative colitis (ABIVAX, data in file). The CBC recruits several factors to m7G-modified transcripts to mediate processing events and is required for efficient cellular and viral pre-mRNA splicing[3]. ABX464 will only act on viral replication once proviral DNA was integrated to cellular DNA This is important as the viral genome, once integrated in infected cells, requires both activation and inhibition of precursor mRNA splicing[18,19]. Inefficient alternative splicing is required to maintain a balance between HIV gene expression and viral production[18,26] This balance is thought to be mediated by the HIV long terminal repeat (LTR) and the presence of suboptimal viral 5′ and 3′ splice sites (5′ and 3′ ss), which are positively regulated by regulatory sequences and their recognition by cognate trans-acting cellular factors[26,27,28,29,30,31,32]. Our findings may open up new treatment options for patients with HIV and inflammatory diseases
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