HIV/AIDS患者迟发型和持续型免疫重建不良的免疫机制研究

Highly active antiretroviral therapy (HAART) could effectively restore peripheral blood CD4 T-cell counts of HIV/AIDS patients, but about 20% of HIV infected individuals, there is no appreciable increase in peripheral blood CD4 T-cell counts, despite suppression of plasma viremia for a long period. These patients are called immunological non-responders (INR). These patients have higher risk of morbidity and mortality compared to HIV-1 patients with optimal CD4 T-cell reconstitution along with virologic control after HAART. Single specific cutoff value of CD4+T-cell count and time on HAART for INR has been set up at present. In the previous studies, we have identified two types of INRs: delayed immune non-responders (DINR) and persistent immune non-responders (PINR). The impaired thymic output and the increased immune activation and exhaustion have been proved to contribute to the pathogenesis of INRs. Thus, we put forward the hypothesis: “the different immunological mechanisms might contribute to the pathogenesis of two types of INRs (DINR and PINR).” In the current study, we will: 1) establish the prospective cohort of AIDS patients receiving HAART more than 4 years, divide these patients into DINRs and PINRs, and analyzed the production of CD4 T cells (thymic output, proliferation and differentiation) and the destruction (immune activation, exhaustion and apoptosis) of CD4 T cells; 2) observe whether the status of immune reconstitution of DINRs and PINRs will change when the treatment for more than 2 years; 3) explore the molecular mechanism of different immune mechanism in different type patients (DINRs and PINRs). These results of the current study will provide the guide for identify INR and provide the evidence for correcting INR in the clinic, and finally decrease the risk of morbidity and mortality.

重建HIV/AIDS患者免疫功能是高效抗逆转录病毒治疗的主要目标。免疫重建不良（INR）严重影响HIV/AIDS患者的临床预后。目前国内外对免疫重建不良的判定采用单一时间界定点和CD4+T细胞数目，忽视了免疫重建是一个动态过程。在前期工作中，我们通过临床分层研究发现免疫重建不良有迟发型（DINR）和持续型（PINR）两种亚型，提出“从CD4 T细胞的生成和破坏两个方面考虑，二者是否存在不同的免疫病理机制”。我们在前期回顾性队列研究基础上，拟继续进行前瞻性研究，通过从胸腺输出功能、生成后增殖和分化评价两个亚型CD4细胞生成能力差异；从免疫活化、抑制性共刺激分子受体表达、凋亡三个方面评价两个亚型CD4破坏差异；观察二者在后期免疫重建情况的转变情况，最终阐明导致不同亚型的免疫分子机制，从而提出有针对性的临床干预措施，减少HIV/AIDS机会性感染和肿瘤的发生率和病死率。

约15%-30%的HIV/AIDS患者在HIV病毒被充分抑制的情况下，外周血CD4+T细胞数目仍无法得到很好的恢复，称免疫重建不良。目前国内外对免疫重建不良的判定采用单一时间界定点和CD4+T细胞数目，忽视了免疫重建是一个动态过程。在前期工作中，我们根据T细胞恢复的动力学，发现免疫重建不良有两种类型：迟发性免疫重建不良（I型，type I IPRs）和持续性免疫重建不良（II型，type II IPRs）。我们在4-5年回顾性研究的基础上，继续对I型和II型免疫重建不良患者进行2年的前瞻性研究，并通过检测其胸腺输出量、活化T细胞和调节性T细胞（Treg）亚群的比例、干扰素刺激基因表达水平以及血浆新喋呤浓度，明确其免疫重建不良的免疫学和分子机制。我们发现I型IPRs胸腺输出功能和T细胞轻度受损，治疗6-7年后，多数患者CD4+T细胞数目可以恢复至理想水平；II型IPRs胸腺输出功能和T细胞严重受损，这类患者经HAART治疗6-7年后，CD4+T细胞数目仍不能达到理想状态。该研究在国际上首次提出免疫重建不良的两种分型，拓宽了学界对免疫重建不良的认识，为开发新的治疗策略提供依据，为更早地发现免疫重建不良提供预警指标，进而减少HIV/AIDS机会性感染和肿瘤的发生率和病死率。