Department of Microbiology and Medical Zoology, School of Medicine, Medical Sciences Campus, University of Puerto Rico, San Juan, PR, 00935, USA.
Department of Pharmacology, University of Puerto Rico, Medical Sciences Campus, San Juan, PR, USA.
Sci Rep. 2022 Jan 7;12(1):233. doi: 10.1038/s41598-021-03896-3.
HIV-associated neurocognitive disorders (HAND) are prevalent despite combined antiretroviral therapy (cART), affecting 52% of people living with HIV. Our laboratory has demonstrated increased expression of cathepsin B (CATB) in postmortem brain tissue with HAND. Increased secretion of CATB from in vitro HIV-infected monocyte-derived macrophages (MDM) induces neurotoxicity. Activation of cannabinoid receptor type 2 (CB2R) inhibits HIV-1 replication in macrophages and the neurotoxicity induced by viral proteins. However, it is unknown if CB2R agonists affect CATB secretion and neurotoxicity in HIV-infected MDM. We hypothesized that HIV-infected MDM exposed to CB2R agonists decrease CATB secretion and neurotoxicity. Primary MDM were inoculated with HIV-1 and treated with selective CB2R agonists JWH-133 and HU-308. HIV-1 p24 and CATB levels were determined from supernatants using ELISA. MDM were pre-treated with a selective CB2R antagonist SR144528 before JWH-133 treatment to determine if CB2R activation is responsible for the effects. Neuronal apoptosis was assessed using a TUNEL assay. Results show that both agonists reduce HIV-1 replication and CATB secretion from MDM in a time and dose-dependent manner and that CB2R activation is responsible for these effects. Finally, JWH-133 decreased HIV/MDM-CATB induced neuronal apoptosis. Our results suggest that agonists of CB2R represent a potential therapeutic strategy against HIV/MDM-induced neurotoxicity.
HIV 相关神经认知障碍（HAND）尽管有联合抗逆转录病毒治疗（cART），仍普遍存在，影响 52%的 HIV 感染者。我们的实验室已经证明 HAND 患者的死后脑组织中组织蛋白酶 B（CATB）表达增加。体外 HIV 感染的单核细胞衍生巨噬细胞（MDM）中 CATB 的分泌增加会导致神经毒性。大麻素受体 2 型（CB2R）的激活可抑制巨噬细胞中的 HIV-1 复制以及病毒蛋白诱导的神经毒性。然而，尚不清楚 CB2R 激动剂是否会影响 HIV 感染的 MDM 中 CATB 的分泌和神经毒性。我们假设，暴露于 CB2R 激动剂的 HIV 感染的 MDM 会减少 CATB 的分泌和神经毒性。原代 MDM 接种 HIV-1 后用选择性 CB2R 激动剂 JWH-133 和 HU-308 处理。使用 ELISA 从上清液中测定 HIV-1 p24 和 CATB 水平。用选择性 CB2R 拮抗剂 SR144528 预处理 MDM 后再用 JWH-133 处理，以确定 CB2R 的激活是否是这些作用的原因。使用 TUNEL 测定法评估神经元凋亡。结果表明，两种激动剂均以时间和剂量依赖的方式减少 MDM 中的 HIV-1 复制和 CATB 分泌，并且 CB2R 的激活是这些作用的原因。最后，JWH-133 减少了 HIV/MDM-CATB 诱导的神经元凋亡。我们的研究结果表明，CB2R 激动剂代表了一种针对 HIV/MDM 诱导的神经毒性的潜在治疗策略。
