586. Dimerization Inhibition of HIV-1 RNA by 2’-Deoxy-2’-fluoro-beta-D-arabinose Nucleic Acid (2’-FANA) Modified Antisense Oligonucleotides Results in Potential Inhibition of Viral Expression
Bibliographic record
Abstract
Human immunodeficiency virus-1 (HIV-1) viral particle contains two copies of genomic RNA, which is known to form dimers via intermolecular interactions. The dimerization process is initiated by the formation of a kissing-loop dimer through base pairing of the palindromic loop sequence within dimerization initiation site (DIS). It has been shown that mutation or inhibitions of the DIS severely affect the viral infectivity. Antisense oligonucleotides (AONs) are single-stranded synthetic oligonucleotides that recognize target RNAs via Watson-Crick base pairing and cause post-translational inhibition. The mechanisms are believed to be RNase H cleavage of target RNA, steric hindrance of the translation machinery or prevention of RNA-RNA or RNA-protein interactions. While AONs offer promising solutions for variety of human diseases in preclinical studies and many of these are currently in clinical studies, a number of challenges still hamper their translation from the bench to the bedside, the most significant of which include target accessibility, off target effects, poor extracellular and intracellular stability and effective delivery into target cells. 2’-deoxy-2’-fluoro-beta-D-arabinose nucleic acid (2’-FANA) modification significantly enhances chemical and intracellular stability, as well as binding to the target RNA, forming stable heteroduplex structures. Moreover, 2’-FANA modification has been shown to facilitate gymnotic cellular delivery, a carrier-free method of achieving cellular uptake. Thus, we hypothesized that 2’-FANA modified AONs that bind HIV-1 DIS can inhibit dimerization, and subsequently inhibit viral expression. Firstly, we tested gymnotic delivery of 2’-FANA modified AONs to peripheral blood mononuclear cells (PBMCs) freshly isolated from human blood. Cellular uptake of the 2’-FANA AONs without any transfection reagent were observed in live-cell confocal microscopy analysis as soon as an hour after adding AONs. Next, the HIV-1 inhibitory effect of the 2’-FANA AONs was tested in HIV-1 infected PBMCs. Cell supernatant was collected and HIV-1 expression was measured by HIV-1 p24 ELISA. The 2’-FANA AONs strongly inhibited HIV-1 expression as long as two weeks after 2’-FANA AONs treatment. A mechanism study showed that the 2’-FANAAONs work against HIV by steric blocking of dimerization. Unlike most oligonucleotide therapeutics, 2’-FANA AONs can be gymnotically delivered into PBMCs. This fact makes 2’-FANA AONs great drug candidates for antiretroviral therapy.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".