Axe Des Maladies Infectieuses Et Immunitaires, Centre de Recherche du CHU de Québec-Université Laval, Pavillon CHUL, Quebec, QC, G1V 4G2, Canada.
Clinique de Planification Des Naissances, CHU de Québec-Université Laval, Pavillon Hôpital Saint-François D'Assise, Quebec, QC, G1L 3L5, Canada.
J Neurovirol. 2021 Apr;27(2):279-301. doi: 10.1007/s13365-021-00955-3. Epub 2021 Mar 1.
HIV-1 infection in the central nervous system (CNS) causes the release of neurotoxic products from infected cells which trigger extensive neuronal loss. Clinically, this results in HIV-1-associated neurocognitive disorders (HAND). However, the effects on neuroprotective factors in the brain remain poorly understood and understudied in this situation. HAND is a multifactorial process involving several players, and the complex cellular mechanisms have not been fully elucidated yet. In this study, we reported that HIV-1 infection of astrocytes limits their potential to express the protective chemokine fractalkine in response to an inflammatory environment. We next confirmed that this effect was not due to a default in its shedding from the cell surface. We then investigated the biological mechanism responsible for this reduced fractalkine expression and found that HIV-1 infection specifically blocks the interaction of transcription factor NF-κB on its promoter with no effect on other cytokines. Moreover, we demonstrated that fractalkine production in astrocytes is regulated in response to immune factors secreted by infected/activated microglia and macrophages. In contrast, we observed that conditioned media from these infected cells also trigger neuronal apoptosis. At last, we demonstrated a strong neuroprotective action of fractalkine on human neurons by reducing neuronal damages. Taken together, our results indicate new relevant interactions between HIV-1 and fractalkine signaling in the CNS. This study provides new information to broaden the understanding of HAND and possibly foresee new therapeutic strategies. Considering its neuro-protective functions, reducing its production from astrocytes could have important outcomes in chronic neuroinflammation and in HIV-1 neuropathogenesis.
HIV-1 感染中枢神经系统（CNS）会导致感染细胞释放出神经毒性产物，从而引发广泛的神经元死亡。临床上，这会导致 HIV-1 相关性认知障碍（HAND）。然而，在这种情况下，大脑中神经保护因子的影响仍知之甚少。HAND 是一个多因素的过程，涉及多个参与者，其复杂的细胞机制尚未完全阐明。在这项研究中，我们报道了 HIV-1 感染星形胶质细胞会限制其在炎症环境下表达保护性趋化因子 fractalkine 的能力。接下来，我们证实这种效应不是由于 fractalkine 从细胞表面脱落的默认机制所致。然后，我们研究了导致 fractalkine 表达减少的生物学机制，发现 HIV-1 感染特异性地阻断了转录因子 NF-κB 与其启动子上的相互作用，而对其他细胞因子没有影响。此外，我们证明了星形胶质细胞中 fractalkine 的产生是对受感染/激活的小胶质细胞和巨噬细胞分泌的免疫因子的反应而调节的。相比之下，我们观察到来自这些感染细胞的条件培养基也会引发神经元凋亡。最后，我们通过减少神经元损伤，证明 fractalkine 对人神经元具有很强的神经保护作用。总之，我们的研究结果表明 HIV-1 和 fractalkine 信号在中枢神经系统中的新的相关相互作用。这项研究为 HAND 的理解提供了新的信息，并可能预见新的治疗策略。考虑到 fractalkine 的神经保护功能，减少星形胶质细胞 fractalkine 的产生可能对慢性神经炎症和 HIV-1 神经发病机制具有重要意义。
