HIV and opiates dysregulate K(+)- Cl(-) cotransporter 2 (KCC2) to cause GABAergic dysfunction in primary human neurons and Tat-transgenic mice.
HIV and opiates dysregulate K(+)- Cl(-) cotransporter 2 (KCC2) to cause GABAergic dysfunction in primary human neurons and Tat-transgenic mice.
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DOI：
10.1016/j.nbd.2020.104878
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发表时间：
2020-07
影响因子：
6.1
通讯作者：
Knapp PE
中科院分区：
文献类型：
--
作者：
Barbour AJ;Hauser KF;McQuiston AR;Knapp PE
大约一半的HIV感染者（PWH）表现出HIV相关的神经病理学（neuroHIV），即使在接受联合抗逆转录病毒治疗时也是如此。阿片类药物的使用在PWH中广泛存在，并加剧了神经HIV。虽然神经元本身没有被感染，但它们会引起亚致死性损伤，并且GABA能破坏选择性地易受感染/受影响的神经胶质释放的病毒和炎症因子的影响。在这里，我们证明了暴露于HIV-1或HIV-1蛋白±吗啡后，原代人类神经元中K+-Cl−协同转运蛋白2（KCC 2）水平降低，导致GABAAR介导的超极化/抑制被破坏。我们发现HIV蛋白达特（通过NMDA受体起作用）和R5-tropic gp 120（通过CCR 5起作用）以及吗啡（通过μ-阿片受体起作用）诱导KCC 2损失。我们证明，修改KCC 2水平或功能，或拮抗NMDAR，CCR 5或莫尔拯救KCC 2和GABAAR介导的超极化/抑制在HIV，达特，或gp 120 ±吗啡暴露的神经元。使用可诱导的Tat转基因小鼠neuroHIV模型，我们发现长期暴露于达特也会降低KCC 2。我们的研究结果确定KCC 2作为一种新的治疗靶点，用于改善神经HIV的病理生物学，特别是暴露于阿片类药物的PWH。
Approximately half of people infected with HIV (PWH) exhibit HIV-associated neuropathology (neuroHIV), even when receiving combined antiretroviral therapy. Opiate use is widespread in PWH and exacerbates neuroHIV. While neurons themselves are not infected, they incur sublethal damage and GABAergic disruption is selectively vulnerable to viral and inflammatory factors released by infected/affected glia. Here, we demonstrate diminished K+-Cl− cotransporter 2 (KCC2) levels in primary human neurons after exposure to HIV-1 or HIV-1 proteins ± morphine, resulting in disruption of GABAAR-mediated hyperpolarization/inhibition. We found that the HIV proteins Tat (acting through NMDA receptors), and R5-tropic gp120 (acting via CCR5), and morphine (acting through μ-opioid receptors) induce KCC2 loss. We demonstrate that modifying KCC2 levels or function, or antagonizing NMDAR, CCR5 or MOR rescues KCC2 and GABAAR-mediated hyperpolarization/inhibition in HIV, Tat, or gp120 ± morphine-exposed neurons. Using an inducible, Tat-transgenic mouse neuroHIV model, we found that chronic exposure to Tat also reduces KCC2. Our results identify KCC2 as a novel therapeutic target for ameliorating the pathobiology of neuroHIV, especially PWH exposed to opiates.
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DOI：
10.1097/qai.0b013e318229ba41
发表时间：
2011-10-01
期刊：
Journal of acquired immune deficiency syndromes (1999)
影响因子：
--
作者：
Byrd DA;Fellows RP;Morgello S;Franklin D;Heaton RK;Deutsch R;Atkinson JH;Clifford DB;Collier AC;Marra CM;Gelman B;McCutchan JA;Duarte NA;Simpson DM;McArthur J;Grant I;CHARTER Group
通讯作者：
CHARTER Group
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
7.7
作者：
Chen, Ming;Wang, Jinzhao;Yang, Li
通讯作者：
Yang, Li
影响因子：
25
作者：
Ferrini F;Trang T;Mattioli TA;Laffray S;Del'Guidice T;Lorenzo LE;Castonguay A;Doyon N;Zhang W;Godin AG;Mohr D;Beggs S;Vandal K;Beaulieu JM;Cahill CM;Salter MW;De Koninck Y
通讯作者：
De Koninck Y
影响因子：
64.5
作者：
Chen B;Li Y;Yu B;Zhang Z;Brommer B;Williams PR;Liu Y;Hegarty SV;Zhou S;Zhu J;Guo H;Lu Y;Zhang Y;Gu X;He Z
通讯作者：
He Z