Gene-based therapies represent a promising treatment for HIV-1 infection, as they offer the potential for sustained viral inhibition and reduced treatment interventions. One approach developed here involves using conditionally replicating vectors (CR-vectors). CR-vectors utilize HIV-expressed proteins to replicate and disseminate along with HIV into the budding viral particles, thereby co-infecting target cellular reservoirs. We generated and characterized several CR-vectors carrying various therapeutic payloads of non-coding RNAs targeted to HIV-1; both transcriptionally and post-transcriptionally. Both virus and vector expression was followed in cell culture systems and T-cells in the presence and absence of mycophenolic acid (MPA) selection. We find here that CR-vectors functionally suppress HIV expression in a long-term stable manner and that transcriptional targeting of and epigenetic silencing of HIV can be passaged to newly infected cells by the action of the CR-vector, ultimately establishing a sustained parasitism of HIV. Our findings suggest that CR-vectors with modulatory non-coding RNAs may be a viable approach to achieving long-term sustained suppression of HIV-1 leading ultimately to a functional cure.

基于基因的疗法代表了对HIV-1感染的有前途的治疗方法，因为它们提供了持续抑制病毒和减少治疗干预的潜力。这里开发的一种方法涉及使用条件复制向量（CR向量）。CR载体利用表达HIV的蛋白质与HIV复制并传播到发芽的病毒颗粒中，从而共同感染靶细胞储库。我们生成并表征了几种带有针对HIV-1的非编码RNA的各种治疗有效载荷的CR载体；转录和转录后。在存在和不存在霉酚酸（MPA）选择的情况下，在细胞培养系统和T细胞中跟踪病毒和载体的表达。我们在这里发现，CR载体在功能上长期稳定地抑制了HIV的表达，HIV的转录靶向和表观沉默可以通过CR载体的作用传递给新感染的细胞，最终建立了持续的寄生虫病。艾滋病病毒。我们的发现表明，具有调节性非编码RNA的CR载体可能是实现HIV-1长期持续抑制的一种可行方法，最终导致了功能性治愈。