Expression of Human Immunodeficiency Virus Transactivator of Transcription (HIV-Tat(1-86)) Protein Alters Nociceptive Processing that is Sensitive to Anti-Oxidant and Anti-Inflammatory Interventions.
Expression of Human Immunodeficiency Virus Transactivator of Transcription (HIV-Tat(1-86)) Protein Alters Nociceptive Processing that is Sensitive to Anti-Oxidant and Anti-Inflammatory Interventions.
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DOI：
10.1007/s11481-021-09985-4
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发表时间：
2022-06
期刊：
影响因子：
--
通讯作者：
McLaughlin JP
中科院分区：
文献类型：
--
作者：
Cirino TJ;Alleyne AR;Duarte V;Figueroa A;Simons CA;Anceaume EM;Kendrick J;Wallman O;Eans SO;Stacy HM;Medina JM;McLaughlin JP
尽管联合抗逆转录病毒治疗（cART）在降低病毒载量方面取得了成功，但很大一部分人类免疫缺陷病毒（HIV）阳性患者报告慢性疼痛。即使无法检测到病毒载量，这种共发病的确切机制仍不清楚，但转录反激活子（HIV-Tat）蛋白引起了特别的兴趣。功能性HIV-Tat蛋白甚至可以在病毒载量检测不到的患者脑脊液中观察到。据推测，Tat蛋白暴露足以通过激活小胶质细胞和产生氧化应激诱导神经性疼痛样表现。iTat小鼠在每日给予强力霉素（100mg /kg/d, i.p，长达14天）后中枢神经系统有条件地表达Tat（1-86）蛋白。HIV-Tat蛋白暴露对动物健康的影响，分别用蔗糖诱发的梳理和急性筑巢行为来评估疼痛抑制行为，用热水断尾和von Frey试验来评估热痛觉过敏和机械异常性疼痛的发展。在选择的时间点采集的组织被用来评估氧化应激、星形细胞增生和小胶质细胞增生以及血脑屏障完整性的体外改变，使用基于荧光的指标进行检测。该蛋白引起轻度热痛觉过敏，但在暴露4天后开始出现强烈的机械异常性疼痛，7天后达到最低点。伤害性加工的变化与蔗糖诱发的梳理行为减少有关，但不改变急性筑巢行为；通过DCF荧光强度测量脊髓自由基生成失调，胶质细胞标志物Iba-1和GFAP的免疫组织化学表达改变，血脑屏障对小分子荧光示踪剂荧光素钠的通透性以时间依赖性的方式增加。在每日注射强力霉素（100 mg/kg/d）前30分钟用抗炎药吲哚美辛（1 mg/kg/d, i.p）、抗氧化剂甲基磺酰甲烷（100 mg/kg/d i.p）或免疫调节剂富马酸二甲酯（100 mg/kg/d p.p）预处理7天，可显著减轻ta诱导的机械异位性疼痛的发生。总的来说，这些数据表明，即使急性暴露于病理相关水平的HIV-1 Tat蛋白，也足以产生与hiv阳性患者报告的慢性疼痛一致的神经生理和行为表现。
Despite the success of combined antiretroviral therapy (cART) in reducing viral load, a substantial portion of Human Immunodeficiency Virus (HIV)+ patients report chronic pain. The exact mechanism underlying this co-morbidity even with undetectable viral load remains unknown, but the transactivator of transcription (HIV-Tat) protein is of particular interest. Functional HIV-Tat protein is observed even in cerebrospinal fluid of patients who have an undetectable viral load. It is hypothesized that Tat protein exposure is sufficient to induce neuropathic pain-like manifestations via both activation of microglia and generation of oxidative stress. iTat mice conditionally expressed Tat(1–86) protein in the central nervous system upon daily administration of doxycycline (100 mg/kg/d, i.p., up to 14 days). The effect of HIV-Tat protein exposure on the well-being of the animal was assessed using sucrose-evoked grooming and acute nesting behavior for pain-depressed behaviors, and the development of hyperalgesia assessed with warm-water tail withdrawal and von Frey assays for thermal hyperalgesia and mechanical allodynia, respectively. Tissue harvested at select time points was used to assess ex vivo alterations in oxidative stress, astrocytosis and microgliosis, and blood-brain-barrier integrity with assays utilizing fluorescent-based indicators. Tat protein induced mild thermal hyperalgesia but robust mechanical allodynia starting after 4 days of exposure, reaching a nadir after 7 days. Changes in nociceptive processing were associated with reduced sucrose-evoked grooming behavior without altering acute nesting behavior; and in spinal cord dysregulated free radical generation as measured by DCF fluorescent intensity, altered immunohistochemical expression of the gliotic markers, Iba-1 and GFAP, and increased permeability of the blood-brain-barrier to the small molecule fluorescent tracer, sodium fluorescein in a time-dependent manner. Pretreatment with the anti-inflammatory, indomethacin (1 mg/kg/d, i.p), the antioxidant, methylsulfonylmethane (100 mg/kg/d i.p) or the immunomodulatory agent, dimethylfumarate (100 mg/kg/d p.o) thirty minutes prior to daily injections of doxycycline (100 mg/kg/d i.p) over 7 days significantly attenuated the development of Tat-induced mechanical allodynia. Collectively, the data suggests that even acute exposure to HIV-1 Tat protein at pathologically relevant levels is sufficient to produce select neurophysiological and behavioral manifestations of chronic pain consistent with that reported by HIV-positive patients.
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影响因子：
4.8
作者：
Deuis JR;Dvorakova LS;Vetter I
通讯作者：
Vetter I
DOI：
10.1073/pnas.1308673110
发表时间：
2013-08-13
影响因子：
11.1
作者：
Johnson, Tory P.;Patel, Karan;Nath, Avindra
通讯作者：
Nath, Avindra
影响因子：
5.6
作者：
Cirino, Thomas J.;Eans, Shainnel O.;McLaughlin, Jay P.
通讯作者：
McLaughlin, Jay P.
影响因子：
6
作者：
Kim, BO;Liu, Y;He, JJ
通讯作者：
He, JJ
影响因子：
4.8
作者：
Acharjee, Shaona;Noorbakhsh, Farshid;Power, Christopher
通讯作者：
Power, Christopher