Instituto de Investigaciones Biomédicas en Retrovirus y Sida, Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina.
J Neurosci Res. 2014 Feb;92(2):267-74. doi: 10.1002/jnr.23294. Epub 2013 Nov 19.
Although HIV-associated neurocognitive disorders (HAND) result from injury and loss of neurons, productive infection routinely takes place in cells of macrophage lineage. In such a complex context, astrocytosis induced by local chemokines/cytokines is one of the hallmarks of HIV neuropathology. Whether this sustained astrocyte activation is able to alter telomere-aging process is unknown. We hypothesized that interaction of HIV with astrocytes may impact astrocyte telomerase activity (TA) and telomere length in a scenario of astrocytic activation measured by expression of glial fibrillary acidic protein (GFAP). To test this hypothesis, cultured murine astrocytes were challenged with pseudotyped HIV/vesicular stomatitis virus (HIV/VSV) to circumvent the absence of viral receptors; and GFAP, telomerase activity, and telomere length were quantified. As an early and transient event after HIV infection, both TA activity and telomere length were significantly augmented (P < 0.001). Later, a strong negative correlation (-0.8616, P < 0.0001) between virus production and telomerase activity was demonstrated. Once HIV production had reached a peak (7 dpi), the TA decreased, showing levels similar to those of noninfected cells. In contrast, the astrocyte became activated, exhibiting significantly increased levels of GFAP expression directly related to the level of HIV/VSV replication (P < 0.0001). Our results suggest that HIV-infected astrocytes exhibit early disturbance in their cellular functions, such as telomerase activity and telomere length, that may attenuate cell proliferation and enhance the astrocyte dysregulation, contributing to HIV neuropathogenesis. Understanding the mechanisms involved in HIV-mediated persistence by altering the telomere-related aging processes could aid in the development of therapeutic modalities for neurological complications of HIV infection.
虽然 HIV 相关的神经认知障碍（HAND）是由神经元损伤和丧失引起的，但 HIV 的感染通常发生在巨噬细胞谱系的细胞中。在这种复杂的情况下，局部趋化因子/细胞因子诱导的星形胶质细胞增生是 HIV 神经病理学的标志之一。尚不清楚这种持续的星形胶质细胞激活是否能够改变端粒衰老过程。我们假设，HIV 与星形胶质细胞的相互作用可能会影响星形胶质细胞端粒酶活性（TA）和端粒长度，而星形胶质细胞激活的指标是胶质纤维酸性蛋白（GFAP）的表达。为了验证这一假设，我们用假型 HIV/水疱性口炎病毒（HIV/VSV）来挑战培养的鼠星形胶质细胞，以规避病毒受体的缺失；并对 GFAP、端粒酶活性和端粒长度进行了量化。作为 HIV 感染后的早期和短暂事件，TA 活性和端粒长度都显著增加（P<0.001）。之后，证明了病毒产生与端粒酶活性之间存在强烈的负相关（-0.8616，P<0.0001）。一旦 HIV 产量达到峰值（7dpi），TA 就会下降，表现出与未感染细胞相似的水平。相比之下，星形胶质细胞被激活，GFAP 的表达水平显著增加，这与 HIV/VSV 复制水平直接相关（P<0.0001）。我们的研究结果表明，HIV 感染的星形胶质细胞表现出早期的细胞功能紊乱，如端粒酶活性和端粒长度的紊乱，这可能会减弱细胞增殖，并增强星形胶质细胞失调，从而促进 HIV 神经发病机制。了解 HIV 介导的持续性改变与端粒相关的衰老过程相关的机制，可能有助于开发针对 HIV 感染的神经并发症的治疗方法。
