Long lasting control of viral rebound with a new drug ABX464 targeting Rev - mediated viral RNA biogenesis.
Long lasting control of viral rebound with a new drug ABX464 targeting Rev - mediated viral RNA biogenesis.
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DOI：
10.1186/s12977-015-0159-3
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发表时间：
2015-04-09
期刊：
影响因子：
3.3
通讯作者：
Tazi J
中科院分区：
文献类型：
--
作者：
Campos N;Myburgh R;Garcel A;Vautrin A;Lapasset L;Nadal ES;Mahuteau-Betzer F;Najman R;Fornarelli P;Tantale K;Basyuk E;Séveno M;Venables JP;Pau B;Bertrand E;Wainberg MA;Speck RF;Scherrer D;Tazi J
目前的疗法已成功控制艾滋病的流行。然而，仍然需要新药，特别是那些通过新的、尚未探索的作用机制来实现艾滋病毒感染治愈的药物。我们利用原病毒基因组的独特特征，需要激活和抑制病毒转录本的剪接，以开发能够通过抑制 Rev 介导的病毒 RNA 生物合成对人源化小鼠模型中的病毒复制产生持久影响的分子。目前的艾滋病毒疗法可在治疗期间减少病毒载量，但在治疗停止后滴度会反弹。我们设计了一种新药，在病毒载量减少后具有持久效果。我们在此证明，ABX464 会损害不同亚型临床分离株的 HIV 复制，而不会选择 PBMC 或巨噬细胞中的耐药性。单独使用 ABX464 也能有效地损害两种感染 HIV 的人源化小鼠模型中的病毒增殖，这些模型需要 3TC、拉替拉韦和替诺福韦 (HAART) 的组合才能在当前方案中实现病毒抑制。至关重要的是，虽然停止HAART治疗一周后病毒载量急剧增加，但停止ABX464治疗后仅观察到轻微反弹，并且在停止治疗后两个月内反弹幅度一直低于HAART。使用可视化活细胞中单个 HIV RNA 分子的系统，我们发现 ABX464 通过阻止 Rev 介导的未剪接 HIV-1 转录物向细胞质的输出以及通过与帽结合复合物 (CBC) 相互作用来抑制病毒复制。对处理细胞中的病毒 RNA 进行深度测序，发现保留的病毒 RNA 被大量剪接，但重要的是，正常细胞剪接不受药物影响。 ABX464 对人体始终无毒，因此是对当前 HIV 疗法的有希望的补充。 ABX464 代表了一类具有独特特性的新型抗 HIV 分子。 ABX464 在人源化小鼠中具有持久的作用，并中和受感染免疫细胞（包括储存库）的 HIV-1 前病毒基因组的表达，因此它是一种有前途的 HIV 功能性治愈药物。本文的在线版本 (doi:10.1186/s12977-015-0159-3) 包含补充材料，可供授权用户使用。
Current therapies have succeeded in controlling AIDS pandemic. However, there is a continuing need for new drugs, in particular those acting through new and as yet unexplored mechanisms of action to achieve HIV infection cure. We took advantage of the unique feature of proviral genome to require both activation and inhibition of splicing of viral transcripts to develop molecules capable of achieving long lasting effect on viral replication in humanized mouse models through inhibition of Rev-mediated viral RNA biogenesis. Current HIV therapies reduce viral load during treatment but titers rebound after treatment is discontinued. We devised a new drug that has a long lasting effect after viral load reduction. We demonstrate here that ABX464 compromises HIV replication of clinical isolates of different subtypes without selecting for drug resistance in PBMCs or macrophages. ABX464 alone, also efficiently compromised viral proliferation in two humanized mouse models infected with HIV that require a combination of 3TC, Raltegravir and Tenofovir (HAART) to achieve viral inhibition in current protocols. Crucially, while viral load increased dramatically just one week after stopping HAART treatment, only slight rebound was observed following treatment cessation with ABX464 and the magnitude of the rebound was maintained below to that of HAART for two months after stopping the treatment. Using a system to visualize single HIV RNA molecules in living cells, we show that ABX464 inhibits viral replication by preventing Rev-mediated export of unspliced HIV-1 transcripts to the cytoplasm and by interacting with the Cap Binding Complex (CBC). Deep sequencing of viral RNA from treated cells established that retained viral RNA is massively spliced but importantly, normal cellular splicing is unaffected by the drug. Consistently ABX464 is non-toxic in humans and therefore represents a promising complement to current HIV therapies. ABX464 represents a novel class of anti-HIV molecules with unique properties. ABX464 has a long lasting effect in humanized mice and neutralizes the expression of HIV-1 proviral genome of infected immune cells including reservoirs and it is therefore a promising drug toward a functional cure of HIV. The online version of this article (doi:10.1186/s12977-015-0159-3) contains supplementary material, which is available to authorized users.
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