Table_3_Aminobisphosphonates reactivate the latent reservoir in people living with HIV-1.xlsx

Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy. Current research efforts to cure HIV-1 infection include “shock and kill” strategies to disrupt latency using small molecules or latency-reversing agents (LRAs) to induce expression of HIV-1 enabling cytotoxic immune cells to eliminate infected cells. The modest success of current LRAs urges the field to identify novel drugs with increased clinical efficacy. Aminobisphosphonates (N-BPs) that include pamidronate, zoledronate, or alendronate, are the first-line treatment of bone-related diseases including osteoporosis and bone malignancies. Here, we show the use of N-BPs as a novel class of LRA: we found in ex vivo assays using primary cells from ART-suppressed people living with HIV-1 that N-BPs induce HIV-1 from latency to levels that are comparable to the T cell activator phytohemagglutinin (PHA). RNA sequencing and mechanistic data suggested that reactivation may occur through activation of the activator protein 1 signaling pathway. Stored samples from a prior clinical trial aimed at analyzing the effect of alendronate on bone mineral density, provided further evidence of alendronate-mediated latency reversal and activation of immune effector cells. Decay of the reservoir measured by IPDA was however not detected. Our results demonstrate the novel use of N-BPs to reverse HIV-1 latency while inducing immune effector functions. This preliminary evidence merits further investigation in a controlled clinical setting possibly in combination with therapeutic vaccination.

由于潜伏性HIV-1细胞储库在抗逆转录病毒治疗（ART）期间仍持续存在，因此该疗法无法实现HIV-1感染的根治。当前针对HIV-1感染治愈的研究策略主要包括“激活-清除”方案：通过小分子化合物或潜伏逆转试剂（LRAs）打破病毒潜伏状态，诱导HIV-1基因表达，使细胞毒性免疫细胞能够清除被感染的细胞。现有LRAs的临床疗效欠佳，促使学界亟需发掘临床效果更优的新型药物。
氨基双膦酸盐（N-BPs）涵盖帕米膦酸、唑来膦酸及阿仑膦酸，是骨质疏松症、骨恶性肿瘤等骨相关疾病的一线治疗用药。本研究证实，N-BPs可作为一类新型LRAs：在取自接受ART抑制治疗的HIV-1感染者的原代细胞体外实验中，我们发现N-BPs诱导的HIV-1潜伏逆转效率可与T细胞激活剂植物血凝素（PHA）相媲美。RNA测序及机制研究数据表明，该病毒激活过程可能通过激活激活蛋白1信号通路实现。
一项既往旨在评估阿仑膦酸对骨密度影响的临床试验留存样本，进一步验证了阿仑膦酸介导的潜伏逆转及免疫效应细胞激活效应，但未检测到通过IPDA测得的病毒储库衰减。本研究结果证实，N-BPs可在诱导免疫效应细胞功能的同时实现HIV-1潜伏逆转。该初步研究证据表明，需在受控临床环境中开展进一步研究，或可联合治疗性疫苗进行探索。