Veterans Medical Research Foundation, San Diego, California, USA.
Department of Medicine, University of California, San Diego, California, USA.
J Virol. 2023 Feb 28;97(2):e0163022. doi: 10.1128/jvi.01630-22. Epub 2023 Jan 31.
Low level HIV transcription during modern antiretroviral therapy (ART) in persons with HIV is linked to residual inflammation and associated diseases, like cardiovascular disease and cancer. The "block and lock" approach to hold HIV in a state of deep latency may help decrease residual inflammation in a person with HIV on ART and thus improve health. A camptothecin analog topotecan (TPT) was previously implicated as an inhibitor of active HIV replication. Using an primary T cell model of HIV latency, we demonstrated that (i) TPT reduces HIV transcriptional activity in latently infected cells; (ii) downregulation of HIV RNA by TPT cannot be reversed by latency reversing agents; (iii) several primary and secondary mechanism of action of TPT may be involved in control of HIV replication; (iv) regulation of HIV RNA by TPT is dependent on splicing complexity; (v) increase in proportion of unspliced HIV transcripts was facilitated by intron retention and upregulation of splicing factors, specifically , by TPT. Although high TPT dosing (10 μM) was needed to achieve the observed effects, viability of primary CD4 T cells was not greatly affected. Because toxicity can be observed with TPT in persons with cancer, TPT is unlikely to be used as an anti-HIV agent in clinic, but our study provides proof that camptothetin has "block and lock" activity. Other camptothetin analogs, which are less toxic than TPT, should be designed and tested as HIV "block and lock" agents. HIV survives in a state of very low activity, called latency, for long periods in persons with HIV on antiretroviral therapy. This low activity of HIV is linked to residual inflammation and associated diseases, such as heart disease and cancer. New strategies are being explored to further silence the HIV provirus and suppress residual inflammation. This study provides strong evidence that the camptothetin analog, Topotecan, can reduce residual activity of HIV in an experimental model of HIV latency. While Topotecan itself is likely not suitable for use in the clinic due to its toxicity, other camptothetin analogs should be designed and investigated as "block and lock" agents.
在接受抗逆转录病毒疗法 (ART) 的 HIV 感染者中，HIV 转录水平低与残留炎症以及相关疾病（如心血管疾病和癌症）有关。“阻断和锁定”方法可使 HIV 处于深度潜伏状态，从而可能有助于降低接受 ART 的 HIV 感染者的残留炎症，进而改善健康。先前有研究表明，喜树碱类似物拓扑替康（TPT）可抑制 HIV 的复制。本研究使用 HIV 潜伏的原代 T 细胞模型，发现：（i）TPT 降低潜伏感染细胞中的 HIV 转录活性；（ii）TPT 下调的 HIV RNA 不能被逆转录病毒潜伏期逆转剂逆转；（iii）TPT 可能通过几种原初和继发作用机制来控制 HIV 复制；（iv）TPT 对 HIV RNA 的调节依赖于剪接的复杂性；（v）通过内含子保留和剪接因子的上调，尤其是 TPT，促进未剪接 HIV 转录本比例增加。虽然需要高 TPT 剂量（10 μM）才能观察到观察到的效果，但原代 CD4 T 细胞的活力并没有受到很大影响。由于在癌症患者中观察到 TPT 的毒性，TPT 不太可能在临床上用作抗 HIV 药物，但本研究提供了证据，证明喜树碱具有“阻断和锁定”活性。其他毒性低于 TPT 的喜树碱类似物应被设计并作为 HIV“阻断和锁定”药物进行测试。
在接受抗逆转录病毒治疗的 HIV 感染者中，HIV 以一种非常低的活性（称为潜伏）状态存活很长时间。这种 HIV 的低活性与残留炎症和相关疾病（如心脏病和癌症）有关。目前正在探索新的策略，以进一步沉默 HIV 前病毒并抑制残留炎症。本研究提供了强有力的证据，表明喜树碱类似物拓扑替康（Topotecan）可以降低 HIV 潜伏实验模型中的 HIV 残留活性。虽然由于其毒性，拓扑替康本身不太可能在临床上使用，但应设计和研究其他喜树碱类似物作为“阻断和锁定”药物。
