Department of Microbiology and Immunology, University of Western Ontario, London, Ontario N6A 5C1, Canada; Division of Infectious Diseases, Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, United States.
Department of Microbiology and Immunology, University of Western Ontario, London, Ontario N6A 5C1, Canada.
EBioMedicine. 2020 Sep;59:102853. doi: 10.1016/j.ebiom.2020.102853. Epub 2020 Jul 9.
During combined anti-retroviral treatment, a latent HIV reservoir persists within resting memory CD4 T cells that initiates viral recrudescence upon treatment interruption. Strategies for HIV-1 cure have largely focused on latency reversing agents (LRAs) capable of reactivating and eliminating this viral reservoir. Previously investigated LRAs have largely failed to achieve a robust latency reversal sufficient for reduction of latent HIV pool or the potential of virus-free remission in the absence of treatment.
We utilize a polyvalent virus-like particle (VLP) formulation called Activator Vector (ACT-VEC) to 'shock' provirus into transcriptional activity. Ex vivo co-culture experiments were used to evaluate the efficacy of ACT-VEC in relation to other LRAs in individuals diagnosed and treated during the acute stage of infection. IFN-γ ELISpot, qRT-PCR and Illumina MiSeq were used to evaluate antigenicity, latency reversal, and diversity of induced virus respectively.
Using samples from HIV patients diagnosed and treated at acute/early infection, we demonstrate that ACT-VEC can reverse latency in HIV infected CD4 T cells to a greater extent than other major recall antigens as stimuli or even mitogens such as PMA/Iono. Furthermore, ACT-VEC activates more latent HIV-1 than clinically tested HDAC inhibitors or protein kinase C agonists.
Taken together, these results show that ACT-VEC can induce HIV reactivation from latently infected CD4 T cells collected from participants on first line combined antiretroviral therapy for at least two years after being diagnosed and treated at acute/early stage of infection. These findings could provide guidance to possible targeted cure strategies and treatments.
NIH and CIHR.
在联合抗逆转录病毒治疗期间，潜伏的 HIV 储库存在静止记忆 CD4 T 细胞中持续存在，在治疗中断时会引发病毒复发。HIV-1 治愈的策略主要集中在能够重新激活和消除这种病毒储库的潜伏逆转剂（LRA）上。以前研究过的 LRA 基本上未能实现足够强大的潜伏期逆转，以减少潜伏 HIV 池或在没有治疗的情况下实现无病毒缓解的潜力。
我们利用一种称为激活载体（ACT-VEC）的多价病毒样颗粒（VLP）制剂来“冲击”前病毒进入转录活性。体外共培养实验用于评估 ACT-VEC 相对于其他 LRA 在急性感染期间诊断和治疗的个体中的疗效。IFN-γ ELISpot、qRT-PCR 和 Illumina MiSeq 分别用于评估抗原性、潜伏期逆转和诱导病毒的多样性。
使用从急性/早期感染期间诊断和治疗的 HIV 患者的样本，我们证明 ACT-VEC 可以比其他主要回忆抗原更有效地逆转 HIV 感染的 CD4 T 细胞的潜伏期，甚至比 PMA/Iono 等有丝分裂原更有效。此外，ACT-VEC 激活的潜伏 HIV-1 比临床测试的 HDAC 抑制剂或蛋白激酶 C 激动剂更多。
综上所述，这些结果表明，ACT-VEC 可以从接受一线联合抗逆转录病毒治疗的参与者中收集的潜伏感染的 CD4 T 细胞中诱导 HIV 重新激活，这些参与者在急性/早期感染阶段被诊断和治疗后至少两年。这些发现可为可能的靶向治愈策略和治疗提供指导。
NIH 和 CIHR。
