中国科学院昆明动物研究所机构知识库

由于HAART疗法延长了HIV感染者和艾滋病人的预期寿命，以及新发感染老年人快速增长，现今艾滋病老龄化趋势日益严峻。老年艾滋病患者在治疗后的免疫重建效果并不理想，现今又缺乏具有针对性的防治措施。我们实验室用SIV mac239感染老年中国猕猴，建立了老年AIDS猕猴模型，在此基础上探索老年中国猕猴SIV感染的发病机制，并进一步探索有效的、具有针对性的老年艾滋患者治疗策略。本论文在老年AIDS猕猴模型早期感染（前3个月）研究的基础上，继续研究感染慢性期老年中国猕猴疾病进程相关和免疫相关指标。感染早期的研究已经发现，老年组感染SIV后疾病进程更快，免疫衰老在其中发挥关键作用。我们在慢性期的研究发现：（1）老年猴的疾病进展较为严重；（2）Th细胞控制疾病的能力弱于年轻组；（3）老年猴的免疫紊乱在感染SIV后较年轻猴更为严重，尤其是在慢性期，老年组表现出一种更为迅速也更为严重的免疫紊乱。老年猴在SIV感染后最主要的疾病特征就是CD4+ T细胞大量且快速的缺失，以及持续的炎症和免疫活化。而在HIV感染过程中，细胞焦亡是CD4+ T细胞缺失的最主要的方式，且伴随着炎症因子以及细胞内容物的释放，是一种高度炎症性的细胞死亡方式。因此，我们假说细胞焦亡可能是促进老年猴SIV感染后疾病进程和免疫紊乱更为严重的主要因素。为此，我们检测了PBMC中CD4+ T细胞的caspase-1和caspase-3的活化，发现老年组在感染后的细胞焦亡水平上升更为迅速也更为显著，而两组的caspase-3活化水平在感染后虽然也显著上升但没有显著差异。PBMC中的细胞焦亡和caspase-3活化相关基因表达的研究印证了细胞水平的实验结果，肠系膜淋巴结中细胞焦亡和caspase-3活化相关基因的表达结果也显示老年组的细胞死亡更为严重。此外我们进一步分析了细胞焦亡和caspase-3活化与疾病进程和免疫紊乱的相关性。结果无论是在细胞水平还是基因表达水平，细胞焦亡和caspase-3活化都与两组的CD4+ T细胞数量强负相关。值得注意的是，细胞焦亡在老年组表现出与大部分的疾病进展和免疫紊乱指标有较强的相关性，而在年轻组只与部分疾病进展和免疫紊乱表现出相关性。这提示我们，细胞焦亡在老年艾滋病的发病机制中可能发挥重要作用 

As HAART extends the life expectancy of HIV-infected or AIDS patients, and the rapid growth of newly infected elderly people, the aging trend of HIV infection and AIDS is becoming more and more serious. The elderly AIDS patients always have a poor immune reconstruction and lack of targeted prevention and control measures. We have used SIVmac239 infected old Chinese rhesus macaques to establish the old AIDS rhesus macaque model. We further studied the pathogenesis of SIV infection in this model and explored the effective and targeted treatment strategy for the elderly AIDS patients.We have studied the early infection of old AIDS rhesus macaque model previously, and found that older rhesus macaques infected with SIV undergo a faster disease progression, immunosenescence in which plays a key role. In this paper, we continued to study the characteristics of the disease progression and immunity of Chinese rhesus macaque in chronic infection. Our study demonstrated that: (1) the disease progression of older rhesus macaques is more serious; (2) the ability of Th cell in older rhesus macaques to control disease progression is weaker than the younger rhesus macaques; (3) the older rhesus macaques showed a more rapid and more serious immune dysfunction during the chronic phase of infection. One of the most important disease features of the older rhesus macaques after SIV infection is a rapid loss of major CD4+ T cells which is often companied with persistent inflammation and immune activation. Pyroptosis is the most important mechanism to account for the loss of CD4 + T cells after HIV infection by releasing intracellular inflammatory factors and cell contents. Therefore, we hypothesize that pyroptosis may contribute to the more serious disease progression and immune dysfunction in older rhesus macaques. We examined the changes of pyroptosis and apoptosis of CD4+ T cells in PBMCs, and found that pyroptosis in the older rhesus macaques increase more rapidly and significantly after infection, while apoptosis do not show significant differences between the two groups though increased significantly in both groups. The results of pyroptosis and apoptosis-related gene expression in PBMC confirmed the results of the cell-level experiments. The results of pyroptosis and apoptosis-related genes expression in mesenteric lymph nodes also showed that the cell death in the elderly group was more serious.In addition, we further analyzed the relativity between pyroptosis or apoptosis and the disease progression or immune dysfunction. The results from the studies of CD4+T cells or genes expression showed that pyroptosis and apoptosis were negatively correlated with the number of CD4 + T cells in the both two groups. It is noteworthy that the pyroptosis in the older rhesus macaques show strong correlations with most of the markers of disease progression and immune dysfunction, whereas the younger rhesus macaques are associated with only partial markers of the disease progression and immune dysfunction. This suggests that pyroptosis may play an important role in the pathogenesis of elderly HIV-infected or AIDS patients.