Zipeto Donato, Serena Michela, Mutascio Simona, Parolini Francesca, Diani Erica, Guizzardi Elisabetta, Muraro Valentina, Lattuada Emanuela, Rizzardo Sebastiano, Malena Marina, Lanzafame Massimiliano, Malerba Giovanni, Romanelli Maria Grazia, Tamburin Stefano, Gibellini Davide
Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
Department of Diagnostics and Public Health, University of Verona, Verona, Italy.
Front Neurol. 2018 Sep 21;9:791. doi: 10.3389/fneur.2018.00791. eCollection 2018.
AIDS dementia complex (ADC) and HIV-associated neurocognitive disorders (HAND) are complications of HIV-1 infection. Viral infections are risk factors for the development of neurodegenerative disorders. Aging is associated with low-grade inflammation in the brain, i.e., the inflammaging. The molecular mechanisms linking immunosenescence, inflammaging and the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease, are largely unknown. ADC and HAND share some pathological features with AD and may offer some hints on the relationship between viral infections, neuroinflammation, and neurodegeneration. β-microglobulin (βm) is an important pro-aging factor that interferes with neurogenesis and worsens cognitive functions. Several studies published in the 80-90s reported high levels of βm in the cerebrospinal fluid of patients with ADC. High levels of βm have also been detected in AD. Inflammatory diseases in elderly people are associated with polymorphisms of the MHC-I locus encoding HLA molecules that, by associating with βm, contribute to cellular immunity. We recently reported that HLA-C, no longer associated with βm, is incorporated into HIV-1 virions, determining an increase in viral infectivity. We also documented the presence of HLA-C variants more or less stably linked to βm. These observations led us to hypothesize that some variants of HLA-C, in the presence of viral infections, could determine a greater release and accumulation of βm, which in turn, may be involved in triggering and/or sustaining neuroinflammation. ADC is the most severe form of HAND. To explore the role of HLA-C in ADC pathogenesis, we analyzed the frequency of HLA-C variants with unstable binding to βm in a group of patients with ADC. We found a higher frequency of unstable HLA-C alleles in ADC patients, and none of them was harboring stable HLA-C alleles in homozygosis. Our data suggest that the role of HLA-C variants in ADC/HAND pathogenesis deserves further studies. If confirmed in a larger number of samples, this finding may have practical implication for a personalized medicine approach and for developing new therapies to prevent HAND. The exploration of HLA-C variants as risk factors for AD and other neurodegenerative disorders may be a promising field of study.
艾滋病痴呆综合征(ADC)和HIV相关神经认知障碍(HAND)是HIV-1感染的并发症。病毒感染是神经退行性疾病发生的危险因素。衰老与大脑中的低度炎症相关,即炎症衰老。连接免疫衰老、炎症衰老与神经退行性疾病(如阿尔茨海默病(AD)和帕金森病)发病机制的分子机制在很大程度上尚不清楚。ADC和HAND与AD有一些共同的病理特征,可能为病毒感染、神经炎症和神经退行性变之间的关系提供一些线索。β-微球蛋白(βm)是一种重要的促衰老因子,它会干扰神经发生并恶化认知功能。80至90年代发表的几项研究报告称,ADC患者脑脊液中的βm水平较高。在AD中也检测到了高水平的βm。老年人的炎症性疾病与编码HLA分子的MHC-I位点的多态性有关,这些多态性通过与βm结合,有助于细胞免疫。我们最近报告说,不再与βm相关的HLA-C被整合到HIV-1病毒颗粒中,导致病毒感染性增加。我们还记录了或多或少与βm稳定相连的HLA-C变体的存在。这些观察结果使我们推测,在病毒感染的情况下,某些HLA-C变体可能会导致βm的释放和积累增加,进而可能参与引发和/或维持神经炎症。ADC是HAND最严重的形式。为了探索HLA-C在ADC发病机制中的作用,我们分析了一组ADC患者中与βm结合不稳定的HLA-C变体的频率。我们发现ADC患者中不稳定HLA-C等位基因的频率较高,且没有一个患者是纯合子携带稳定的HLA-C等位基因。我们的数据表明,HLA-C变体在ADC/HAND发病机制中的作用值得进一步研究。如果在更多样本中得到证实,这一发现可能对个性化医疗方法和开发预防HAND的新疗法具有实际意义。探索HLA-C变体作为AD和其他神经退行性疾病的危险因素可能是一个有前景的研究领域。