HIV-1 Proviral Integration Is Blocked by Agonists to the VpPAC2 Neuroendocrine Receptor.
Bibliographic record
Abstract
Abstract VPAC1 is a 7-transmembrane G-protein-coupled neuroendocrine receptor previously shown to transduce a facilitation signal for HIV-1 infection (Branch DR, et al., AIDS.2002;16:309–319). VPAC2, a related receptor, has been reported to have opposing function when compared to VPAC1 (Xia M, et al., J Immunol.1996;157:1132–1138; Tsutsumi M, et al., Diabetes.2002;51:1453–1460). We therefore examined whether stimulation of VPAC2, in contrast to VPAC1, may act to inhibit HIV-1 infection. Using three different and specific agonists of VPAC2, helodermin, RO 25-1553, and R3P55, daily treatment with low concentrations (10−9M) resulted in ~75% to 95% inhibition of either X4 or R5 HIV-1 productive infection in cell lines or primary peripheral blood mononuclear cells. The agonists VIP, PACAP, and secretin, that stimulate the two other VPAC receptor family members VPAC1 and PAC1, did not inhibit HIV-1 infection. Also, Hut78 cells, that lack VPAC2 and are infected by HIV-1, show no effect of VPAC2 agonists on HIV-1 infection. However, Hut78 cells transfected with human VPAC2 cDNA to overexpress this receptor become resistant to HIV-1 infection when treated with VPAC2 agonists. VPAC2-mediated inhibition of productive HIV-1 infection was not due to effects on CD4 or chemokine co-receptor expression, cell growth, or apoptosis. Treatment with VPAC2 agonists also did not inhibit HIV-1 entry into the host cell. However, compared to untreated or cells treated with VPAC1-specific agonists, VPAC2 stimulation profoundly inhibits HIV-1 proviral DNA integration into the host genome. The block in integration was found to be due to the ability of agonists to VPAC2 to inhibit formation of 2-LTR circles, required for HIV-1 integration within the nucleus. We conclude that VPAC2-specific agonists are strongly inhibitory for productive HIV-1 infection. Furthermore, this inhibition is mediated by suppression of 2-LTR circle formation preventing proviral integration. Agonists of VPAC2 appear to be excellent candidates for future development as possible drugs for the amelioration of treatments aimed at the prevention of HIV/AIDS.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.002 |
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".