背景与目的： 在联合抗反转录病毒治疗（Combined antiretroviral therapy, cART)治疗下，绝 大多数HIV感染者可以达到持续的病毒抑制，但是15-30%的HIV感染者在病毒长 期完全抑制的情况下，CD4+T淋巴细胞数仍不能得到满意的恢复，这种现象称为 免疫重建不全(Incomplete immune reconstitution)，而免疫重建不全的感染者称为免 疫无应答者（Immunenon-responders, INRs)和免疫部分应答者。免疫重建不全发生 的重要机制之一是多种原因所致的免疫激活，而免疫激活又对HIV相关非AIDS并 发症的发生以及HIV储存库的维持起到促进作用。 本研究旨在探究雷公藤，一种临床上在多种自身免疫性疾病中广泛应用的免疫 抑制剂，是否可以抑制慢性期艾滋病免疫重建不全患者的免疫激活，影响其病毒储 存库，并通过与未经雷公藤治疗的免疫重建不良者进行对照，探究雷公藤能否对免 疫重建不全者的CD4+T细胞计数和增长速率起到持续的改善作用。 方法： 从北京协和医院艾滋病诊疗中心选出18例符合免疫重建不全定义的HIV感染 者，在cART基础上加用治疗量的雷公藤多甙片（20mgtid)，持续1年，每3个月 规律随访，1年后停止雷公藤治疗后每6个月随访，收集临床资料并留取外周血标 本，测定外周血T淋巴细胞亚群，留取全血、血浆冻存，后续分别用来测量总HIV- DNA和血浆炎症因子水平。回顾性的从北京协和医院艾滋病诊疗中心的就诊患者 中筛选符合免疫重建不全定义，且年龄与实验组匹配的患者作为对照组，对比实验 组与对照组在雷公藤治疗相应cART治疗时间段内CD4+T细胞增长情况。 结果： 1、雷公藤对免疫重建不全者外周血CD4+T细胞计数的影响 对于实验组患者，雷公藤联合cART治疗12月可使CD4+ T细胞计数显著增长 (由 188±61/pl 增至 272±79/pl，p<0.0001 )。CD4+ T 细胞计数增长以记忆 CD4+ T 细胞为主。实验组平均在cART治疗2.5年加用雷公藤治疗，雷公藤治疗期间CD4+T 细胞计数增长速率较雷公藤治疗前增长速率增高（34.0 cells/mm3/年増至82.0 cells/mm3/年，p=0.077);实验组雷公藤停药后CD4+T细胞增长速率显著低于雷公 藤治疗期间速率（82.0 cells/mm3/年to 23.5 cells/mm3/年）；非雷公藤组cART治疗 0.5-3.5年间CD4+T细胞增长速率为27 cells/mm3/年，显著低于实验组雷公藤治疗 期间CD4+T细胞增长速率（p=0.022)。2、 雷公藤对实验组患者血浆炎症因子的影响 对雷公藤治疗组患者开始加用雷公藤多甙治疗的1年前、雷公藤治疗基线（0 年）、加用雷公藤0.5年、加用雷公藤1年，共4个随访点留取的血浆用液相芯片 法对 13 种炎症因子进行测量。IP-10、MIP-ip、MCP-1、IFN-a2、IL-15、IL-12p40 在加用雷公藤多甙治疗后较治疗前显著下降（至少在雷公藤治疗半年或治疗1年较 雷公藤治疗0年有显著下降，p<0.05)。IP-10与两种干扰素的相关性分析提示，IP- 10浓度与IFNy具有显著正相关性。 3、 雷公藤治疗组患者HIV储存库的变化情况 雷公藤治疗前、治疗中、治疗后免疫重建不全患者HIV储存库的变化率无明显 变化。 结论： 1、 雷公藤多甙可显著提高HIV感染免疫重建不全患者外周血CD4+ T淋巴细 胞计数和CD4+T细胞增长速度，以记忆CD4+ T细胞的增长为主，但CD4+T细胞 计数增长速度的提高在停药后不能持续。 2、 免疫重建不全的患者血浆 IP-10、MIP-1P、MCP-1、IFN-a2、IL-15、IL-12p40 水平在加用雷公藤多甙治疗后较治疗前显著下降，以IP-10下降最为显著；IP-10浓 度与IFNY具有显著正相关性。 3、 雷公藤多甙联合cART治疗对于免疫重建不全患者的HIV储存库未发现有明显影响。

Background and Objectives: With the combined antiretroviral therapy (cART), most HIV infected adults could achieve sustained viral suppression. However, 15-30% of the HIV infected adults could not reach a satisfactory restore in the CD4+ T cell count, even after long term HIV suppression. This condition is coined, incomplete immune reconstitution. Patients with this condition is called immune non-responders (INRs) or inadequate responders (InaRs). One of the most crucial mechanisms causing incomplete immune reconstitution is immune activation, which is also found to be related to HIV associated non-AIDS conditions and the sustainment of HIV reservoir. This study aims to investigate whether TwHF, an immune suppressing agent widely used in the treatments of autoimmune diseases, could downgrade the level of immune activation in patients with incomplete immune reconstitution and affect the HIV reservoir, and to confirm whether TwHF could have a lasting improving effect over the immune reconstitution state of the patients with immune reconstitution failure by comparing the TwHF treated patients with matching non-TwHF treated control patients. Methods: Eighteen HIV infected adults meeting the criteria for incomplete immune reconstitution were selected from the patients at Peking Union Medical College Hospital. A thearputic dosage of TwHF extract was added to their background cART for 12 months, during which, regular follow-ups were made every three months and after ceasing the addition of TwHF follow-ups were made every six months, at which, clinical information was collected and peripheral blood were taken for the measurement of T lymphocyte subsets, and full blood and plasma were stored for HIV-DNA and inflammatory markers measurements respectively. A control group of non-TwHF treated patients with incomplete immune reconstitution were retrospectively selected and matched, then the CD4+ T cell increase slope of these patients was analysed and compared with TwHF treated patients. Results: 1.! The influence of TwHF on the T cell subsets in the patients with incomplete immune reconstitution For patients in the TwHF group, a combined treatment of TwHF and cART for 12 months achieved a significant increase in the CD4+ T cell count (from 188±61/μl to 272±79/μl, p<0.0001). The increase in CD4+ T cell count was mainly due to the recovery memory CD4+ T cell. The TwHF treatment started at 2.5 years of cART treatment in average. The CD4+ T cell increase slope during TwHF treatment is higher than before TwHF treatment (34.0 cells/mm3/y to 82.0 cells/mm3/y􀀌p=0.077); the increase slope after TwHF treatment ceasing is significantly lower than during the TwHF treatment (82.0 cells/mm3/y to 23.5 cells/mm3/y􀀌p=0.029); slope of non-TwHF treated control group during 0.5-3.5 years of cART ws 27 cells/mm3/y, which is significantly lower than the slope of TwHF group during the TwHF treatment (p=0.022). 2.! The influence of TwHF on the plasma inflammation markers of the patients with incomplete immune reconstitution 13 plasma inflammation markers were measured using the stored plasma obtained at 1 year previous than the start point of TwHF treatment, start point of TwHF treatment, 0.5 year and 1 year during TwHF treatment. After the iniatiation of TwHF treatment, IP-10, MIP-1β, MCP-1, IFN-α2, IL-15 and IL-12p40 levels were significantly lowered at at least upon one of the two time points during TwHF treatment, 0.5 year or 1 year (p<0.05). Correlation analyses reveal that out of the two types of IFN, IP-10 level is significantly positively correlated to IFN􀀆 level. 3.! The effect of TwHF on HIV reservoir in the patients with incomplete immune reconstitution No significant change was found within the HIV-DNA slopes before, during and after TwHF treatment. Conclusion: 1.! In patients with incomplete immune reconstitution, TwHF increased the CD4+ T cell count and the CD4+ T cell increase slope significantly. The increase of CD4+ T cell count mainly benefited the recovery of memory CD4+ T cell. The increase in the slope of CD4+ T cell change could not be maintained after ceasing the TwHF treatment. 2.! TwHF treatment lowered IP-10, MIP-1β, MCP-1, IFN-α2, IL-15 and IL-12p40 levels in patients with incomplete immune reconstitution, especially in IP-10, which was found to be significantly correlated to IFN􀀆. 3.! TwHF treatment did not show significant influences over the HIV reservoir of patients with incomplete immune reconstitution.