Moso Michael A, Roche Michael, Cevaal Paula M, Lewin Sharon R
Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity.
Victorian Infectious Diseases Service, The Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity.
Curr Opin HIV AIDS. 2025 Sep 1;20(5):432-440. doi: 10.1097/COH.0000000000000963. Epub 2025 Jul 18.
Recent advances in gene therapy have led to the first clinically approved CRISPR/Cas9 therapy for β-thalassaemia and sickle cell disease. Gene therapy could play an important role in targeting HIV persistence and achieving postintervention HIV control. Here, we review recent updates in CRISPR/Cas9-based HIV gene therapy approaches, including CCR5-editing (protect), proviral targeting (excise or modify), and immune cell engineering (attack).
Recent studies provide additional safety data for use of CRISPR/Cas9-based gene therapies, however low in vivo editing efficiency highlights the need for improved delivery methods. This is particularly relevant for strategies requiring transfection of all HIV-infected cells containing intact proviruses, such as proviral excision. For ex vivo editing approaches, poor engraftment and durability of edited cells present additional challenges. Newer methods such as lipid nanoparticle delivery could provide a mechanism to overcome current limitations with ex vivo and in vivo delivery. Several studies have demonstrated proof-of-concept of combination gene therapy approaches, including gene editing strategies to generate HIV-resistant cells with immune effector functions, providing novel approaches to control and durably suppress viral replication.
Several studies have demonstrated feasibility of gene therapy approaches in achieving postintervention HIV control. Improvements in both ex vivo and in vivo delivery methods are required to progress current gene therapy approaches to the clinic.
基因治疗的最新进展已促成首个获临床批准用于治疗β地中海贫血和镰状细胞病的CRISPR/Cas9疗法。基因治疗在针对HIV潜伏并实现干预后HIV控制方面可能发挥重要作用。在此，我们综述基于CRISPR/Cas9的HIV基因治疗方法的最新进展，包括CCR5编辑（保护）、前病毒靶向（切除或修饰）和免疫细胞工程（攻击）。
近期研究提供了关于使用基于CRISPR/Cas9的基因疗法的更多安全性数据，然而体内编辑效率低凸显了改进递送方法的必要性。这对于需要转染所有含有完整前病毒的HIV感染细胞的策略（如前病毒切除）尤为重要。对于离体编辑方法，编辑细胞的植入不佳和耐久性带来了额外挑战。脂质纳米颗粒递送等新方法可能提供一种机制来克服当前离体和体内递送的局限性。多项研究已证明联合基因治疗方法的概念验证，包括产生具有免疫效应功能的HIV抗性细胞的基因编辑策略，为控制和持久抑制病毒复制提供了新方法。
多项研究已证明基因治疗方法在实现干预后HIV控制方面的可行性。需要改进离体和体内递送方法，以使当前的基因治疗方法进入临床阶段。
