Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL.
Division of Infectious Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL.
J Acquir Immune Defic Syndr. 2022 Dec 15;91(5):485-489. doi: 10.1097/QAI.0000000000003086.
With advances in HIV treatment, people with HIV (PWH) are living longer but experience aging-related comorbidities, including cognitive deficits, at higher rates than the general population. Previous studies have shown alterations in lysosomal proteins in blood from PWH with severe dementia. However, these markers have not been evaluated in PWH with milder neurocognitive impairment. We sought to determine whether levels of the lysosomal cysteine protease cathepsin B (CatB) and its endogenous inhibitor cystatin B (CysB) were altered in PWH with neurocognitive impairment and whether antiretroviral therapy (ART) further influenced these levels. Peripheral blood mononuclear cells were obtained from the tenofovir arm of a multicenter clinical trial in which ART-naive, HIV+ participants received treatment for 48 weeks (ACTG A5303, NCT01400412). PWH were divided by neurocognitive status (eg, with or without neurocognitive impairment) before ART initiation. Intracellular levels of CatB and CysB were measured in T cells and monocytes by means of flow cytometry. Levels of CysB were significantly decreased in both CD4 + T cells and CD8 + T cells after 48 weeks of ART in HIV+ participants without neurocognitive impairment but not in participants with neurocognitive impairment. Levels of CysB were increased in CD14 + monocytes from the participants with neurocognitive impairment after ART. Levels of CysB and CatB positively correlated regardless of HIV, neurocognitive status, or exposure to ART. These findings suggest that CysB has the potential to provide mechanistic insight into HIV-associated neurocognitive disorders or provide a molecular target for systemic monitoring or treatment of neurocognitive impairment in the context of ART and should be investigated further.
随着 HIV 治疗的进步，HIV 感染者（PWH）的寿命延长，但比普通人群更易出现与衰老相关的合并症，包括认知缺陷。先前的研究表明，严重痴呆的 PWH 血液中的溶酶体蛋白发生了改变。然而，这些标志物尚未在 PWH 轻度认知障碍患者中进行评估。我们试图确定神经认知障碍的 PWH 中溶酶体半胱氨酸蛋白酶 CatB（CatB）及其内源性抑制剂胱抑素 B（CysB）的水平是否发生改变，以及抗逆转录病毒治疗（ART）是否进一步影响这些水平。从一项多中心临床试验的替诺福韦治疗组中获得了外周血单核细胞，该临床试验中，未经 ART 治疗的 HIV+参与者接受了 48 周的治疗（ACTG A5303，NCT01400412）。在开始 ART 之前，根据神经认知状况（例如，有无神经认知障碍）将 PWH 分组。通过流式细胞术测量 T 细胞和单核细胞中 CatB 和 CysB 的细胞内水平。在无神经认知障碍的 HIV+参与者中，经过 48 周的 ART 治疗后，CD4+T 细胞和 CD8+T 细胞中的 CysB 水平显着降低，但在有神经认知障碍的参与者中没有降低。ART 后，有神经认知障碍的参与者的 CD14+单核细胞中的 CysB 水平升高。无论 HIV、神经认知状况或是否接触 ART，CysB 和 CatB 的水平均呈正相关。这些发现表明，CysB 有可能为 HIV 相关神经认知障碍提供机制见解，或为 ART 背景下神经认知障碍的系统监测或治疗提供分子靶标，应进一步研究。
