Department of Microbiology and Parasitology, Faculty of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain.
Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, 00133 Roma, Italy.
Int J Mol Sci. 2023 Sep 21;24(18):14364. doi: 10.3390/ijms241814364.
HIV-associated neurocognitive disorders (HANDs) still persist despite improved life expectancy, reduced viral loads, and decreased infection severity. The number of patients affected by HANDs ranges from (30 to 50) % of HIV-infected individuals. The pathological mechanisms contributing to HANDs and the most serious manifestation of the disease, HIV-associated dementia (HAD), are not yet well understood. Evidence suggests that these mechanisms are likely multifactorial, producing neurocognitive complications involving disorders such as neurogenesis, autophagy, neuroinflammation, and mitochondrial dysfunction. Over the years, multiple pharmacological approaches with specific mechanisms of action acting upon distinct targets have been approved. Although these therapies are effective in reducing viral loading to undetectable levels, they also present some disadvantages such as common side effects, the need for administration with a very high frequency, and the possibility of drug resistance. Genetic studies on HANDs provide insights into the biological pathways and mechanisms that contribute to cognitive impairment in people living with HIV-1. Furthermore, they also help identify genetic variants that increase susceptibility to HANDs and can be used to tailor treatment approaches for HIV-1 patients. Identification of the genetic markers associated with disease progression can help clinicians predict which individuals require more aggressive management and by understanding the genetic basis of the disorder, it will be possible to develop targeted therapies to mitigate cognitive impairment. The main goal of this review is to provide details on the epidemiological data currently available and to summarise the genetic (specifically, the genetic makeup of the immune system), transcriptomic, and epigenetic studies available on HANDs to date. In addition, we address the potential pharmacological therapeutic strategies currently being investigated. This will provide valuable information that can guide clinical care, drug development, and our overall understanding of these diseases.
尽管艾滋病毒感染者的预期寿命延长、病毒载量降低和感染严重程度降低，但仍存在与艾滋病毒相关的神经认知障碍 (HANDs)。受 HANDs 影响的患者人数占艾滋病毒感染者的比例为（30 至 50）%。导致 HANDs 和该病最严重表现——艾滋病毒相关痴呆 (HAD) 的病理机制尚未得到很好的理解。有证据表明，这些机制可能是多因素的，会导致涉及神经发生、自噬、神经炎症和线粒体功能障碍等障碍的神经认知并发症。多年来，已经批准了多种具有针对不同靶点的特定作用机制的药理学方法。尽管这些疗法有效降低了病毒载量至无法检测的水平，但它们也存在一些缺点，例如常见的副作用、需要非常高的频率给药以及可能产生耐药性。HANDs 的遗传研究提供了对有助于艾滋病毒感染者认知障碍的生物学途径和机制的深入了解。此外，它们还可以帮助识别增加 HANDs 易感性的遗传变异，并可用于为艾滋病毒-1 患者定制治疗方法。识别与疾病进展相关的遗传标志物可以帮助临床医生预测哪些个体需要更积极的管理，通过了解疾病的遗传基础，有可能开发出靶向治疗来减轻认知障碍。本文综述的主要目的是提供有关当前可用的流行病学数据的详细信息，并总结 HANDs 的遗传（特别是免疫系统的遗传构成）、转录组学和表观遗传学研究，此外，我们还探讨了目前正在研究的潜在药理学治疗策略。这将提供有价值的信息，可以指导临床护理、药物开发以及我们对这些疾病的整体理解。
