Chen Lihua, Al-Harthi Lena, Hu Xiu-Ti
Department of Microbial Pathogens and Immunity, Rush University Medical Center, Chicago, IL, United States.
Front Pharmacol. 2021 Jan 28;11:617149. doi: 10.3389/fphar.2020.617149. eCollection 2020.
Combination antiretroviral therapy (cART) suppresses HIV-1 replication, improves immune function, and prolongs the life of people living with HIV (PLWH). However, cART also induces neurotoxicity that could complicate HIV-induced neurodegeneration while reduce its therapeutic efficacy in treating HIV/AIDS. Triumeq is a first-line cART regimen, which is co-formulated by three antiretroviral drugs (ARVs), lamivudine (3TC), abcavir (ABC), and dolutegravir (DTG). Little is known about potential side effects of ARVs on the brain (including those co-formulating Triumeq), and their mechanisms impacting neuronal activity. We assessed acute () and chronic () effects of Triumeq and co-formulating ARVs on pyramidal neurons in rat brain slices containing the medial prefrontal cortex (mPFC) using patch-clamp recording approaches. We found that acute Triumeq or 3TC significantly increased firing of mPFC neurons in a concentration- and time-dependent manner. This neuronal hyperactivity was associated with enhanced Ca influx through voltage-gated Ca channels (VGCCs). Additionally, chronic treatment with Triumeq for 4 weeks (4 wks) also significantly increased firing and Ca influx via VGCCs in mPFC neurons, which was not shown after 2 wks treatment. Such mPFC neuronal hyperexcitability was not found after 4 weeks treatments of individual ARVs. Further, chronic Triumeq exposure significantly enhanced mRNA expression of low voltage-activated (LVA) L-type Ca channels (Ca1.3 L-channels), while changes in high voltage-activated (HVA) Cav1.2 L-channels were not observed. Collectively, these novel findings demonstrate that chronic cART induces hyperexcitability of mPFC pyramidal neurons by abnormally promoting VGCC overactivation/overexpression of VGCCs (including, but may not limited to, LVA-Ca1.3 L-channels), which could complicate HIV-induced neurotoxicity, and ultimately may contribute to HIV-associated neurocognitive disorders (HAND) in PLWH. Determining additional target(s) of cART in mPFC pyramidal neurons may help to improve the therapeutic strategies by minimizing the side effects of cART for treating HIV/AIDS.
联合抗逆转录病毒疗法（cART）可抑制HIV-1复制，改善免疫功能，并延长HIV感染者（PLWH）的寿命。然而，cART也会诱发神经毒性，这可能会使HIV诱导的神经退行性变复杂化，同时降低其治疗HIV/AIDS的疗效。绥美凯是一种一线cART方案，由三种抗逆转录病毒药物（ARV），即拉米夫定（3TC）、阿巴卡韦（ABC）和多替拉韦（DTG）共同配制而成。关于ARV对大脑的潜在副作用（包括那些共同配制绥美凯的药物）及其影响神经元活动的机制，人们知之甚少。我们使用膜片钳记录方法评估了绥美凯和共同配制的ARV对含有内侧前额叶皮质（mPFC）的大鼠脑片锥体细胞的急性（）和慢性（）影响。我们发现，急性给予绥美凯或3TC会以浓度和时间依赖性方式显著增加mPFC神经元的放电。这种神经元活动亢进与通过电压门控钙通道（VGCC）增强的钙内流有关。此外，用绥美凯慢性治疗4周（4周）也会显著增加mPFC神经元通过VGCC的放电和钙内流，而在治疗2周后未观察到这种情况。在单独使用ARV治疗4周后未发现这种mPFC神经元过度兴奋。此外，长期暴露于绥美凯会显著增强低电压激活（LVA）L型钙通道（Ca1.3 L通道）的mRNA表达，而未观察到高电压激活（HVA）Cav1.2 L通道的变化。总的来说，这些新发现表明，长期cART通过异常促进VGCC的过度激活/过表达（包括但不限于LVA-Ca1.3 L通道）诱导mPFC锥体细胞过度兴奋，这可能会使HIV诱导的神经毒性复杂化，并最终可能导致PLWH出现与HIV相关的神经认知障碍（HAND）。确定cART在mPFC锥体细胞中的其他靶点可能有助于通过最小化cART治疗HIV/AIDS的副作用来改善治疗策略。
