HIV相关认知障碍的神经网络基础及遗传与免疫风险因素研究

HIV-associated neurocognitive disorder (HAND) is an important chronic central nervous system complication among HIV-infected patients. Currently, highly active antiretroviral therapy has not been shown to improve the neurocognitive performance of HAND. In addition, there is no HAND-specific diagnostic methods. Hence, it is urgently needed to identify risk factors and develop effective early warning measures for HAND in order to provide interference accordingly. Cognitive performance is affected by brain structure and function, but there is still no systematic research for the neural network connectivity characteristics of HAND. In this project, we would clarify the structure and functional brain connectivity of HAND, then we would investigate the risk genetic factors of HAND and altered structure network based on our previous GWAS cohort. Subsequently, we seek to explore the immune risk factors, its possible mechanisms and establish an early prediction model of HAND by integrating genetic data, the number and function of cytokines and brain-derived neurotrophic factor, as well as the level of peripheral HIV reservoir. Finally, we will perform an independent sample verification to clarify the risk factors of HAND and optimize the early predictive model. Our study will be helpful for developing scalable tools and precise intervention program for the prevention of HAND.

HIV相关认知障碍（HIV-associated neurocognitive disorder，HAND）是HIV感染者重要的慢性中枢神经系统并发症，目前高效抗反转录病毒治疗尚不能改善HAND的神经认知表现，更缺乏特异性的诊断方法，因此确定HAND的危险因素并建立预警机制对早期干预尤为重要。认知功能受到脑结构和功能的影响，而HAND的脑网络连接特征尚缺乏系统研究。本研究将利用脑网络分析方法，明确HAND脑网络结构和功能连接特征，并利用前期GWAS队列，分析HAND及脑网络改变的遗传风险因素。随后，结合细胞因子、脑源性神经营养因子、外周病毒库水平等因素，探讨HAND的免疫风险因素及可能机制，并构建HAND的预警模型。最后，我们将进行独立样本验证，进一步明确HAND的风险因素并优化预警模型，以开发HAND预警分级策略并为其精准干预方案提供理论基础。

HIV相关认知障碍（HIV-associated neurocognitive disorder，HAND）是HIV感染者重要的慢性中枢神经系统并发症，目前高效抗逆转录病毒治疗尚不能改善HAND的神经认知表现，更缺乏特异性的诊断方法，因此确定HAND的危险因素并建立预警机制对早期干预尤为重要。认知功能受到脑结构和功能的影响，而HAND的脑损伤尚缺乏系统研究。本研究将利用多模态磁共振成像，明确HAND脑损伤特征，并利用前期GWAS队列，分析HAND及脑损伤的遗传风险因素。随后，结合细胞因子、脑源性神经营养因子、外周病毒库水平等因素，探讨HAND的免疫风险因素及可能机制。.本研究发现HAND患者存在广泛的脑萎缩，且随认知受损程度而加重，并与单核细胞异常活化及相关细胞因子水平正相关，与外周HLA-DR+ CD4+ T细胞比例呈正相关，但与BDNF水平负相关；HAND患者中免疫功能受损严重者全脑体积萎缩的趋势更为显著，并且体积缩小的脑区更为广泛，部分特征脑区的萎缩程度与免疫功能紊乱程度正相关；本研究未发现HIV整合DNA水平及SNP与HAND症状严重程度或脑损伤程度有显著关联。本研究为开发HAND预警分级策略及精准干预方案提供理论基础。