cART治疗完全应答HIV-1感染者血浆外泌体对CD8^+T细胞的免疫调节作用及与CD4/CD8比值的相关性

Plasma exosomes immune-regutalion role on CD8^+T cells and its relationship with CD4/CD8 ratio in HIV-infected cART-treated complete responder

目的探究 HIV-1 慢性感染者长期联合抗反转录病毒治疗(combination antiretroviral therapy, cART)后血浆中外泌体的特点,分析其动态变化与患者 CD4/CD8 比值的关系,并探讨其对 CD8+ T 细胞的潜在免疫调节作用。方法入组 cART 后完全应答(complete respond, CR)患者 19 例,根据患者 CD4/CD8 比值分为异常组(CD4/CD8 < 0.8)10 例和复常组(CD4/CD8 > 0.8)9 例,设立健康对照(healthy control, HC)5 例。比较 3 组患者血浆外泌体的浓度,通过体外功能实验观察外泌体对 CD8^+ T 细胞活化水平、分泌细胞因子能力和增殖能力的影响,分析其与 CD4/CD8 比值的关系。结果异常组血浆外泌体浓度显著高于复常组和 HC 组,且 CR 患者外泌体的浓度与 CD4/CD8 比值呈负相关(r =-0.648,P=0.043)。异常组外泌体抑制 CD8^+ T 细胞活化指标 CD38^+HLA-DR+的共表达,且抑制效果与患者CD4/CD8比值相关(r=0.478,P=0.039);异常组血浆外泌体抑制 CD8^+ T 细胞分泌 IFN-γ和 IL-2 ,且抑制效果与患者的 CD4/CD8 比值显著相关(r=0.654,P=0.002;r=0.700,P < 0.001);异常组患者血浆外泌体能够抑制 CD8^+ T 细胞的增殖,且抑制效果与患者 CD4/CD8 比值显著相关(r=0.716,P < 0.001)。结论 CD4/CD8 比值异常患者外泌体能抑制 CD8+ T 细胞的活化、增殖及分泌,提示 CD4/CD8 比值异常的 CR 患者体内升高的外泌体对机体过度的免疫活化和炎症状态具有抑制作用。

Objective To investigate the characteristics of plasma exosomes in chronically HIV-infected patients who received long-term combination antiretroviral therapy (cART), to analyze the relationship between dynamic changes of plasma exosomes and CD4/ CD8 ratio, and to explore the potential immune-regulation role of plasma exosomes on CD8+ T cells. Methods Nineteen complete responders (CR) received cART were enrolled and divided into abnormal group (CD4/CD8<0.8, n=10) and normalized group (CD4/CD8>0.8, n=9) according to the CD4/CD8 ratio. Five healthy controls (HC) were also enrolled. The concentrations of plasma exosomes in 3 groups (n=5 per group) were compared, the effects of plasma exosomes on the activation, cytokine secretion and proliferation on CD8+ T cells were investigated through in vitro functional experiment. The relationship between plasma exosomes and CD4/CD8 ratio was analyzed. Results The concentration of plasma exosomes in abnormal group was significantly higher than that in normalized group and the HC group, and negatively correlated with the CD4/CD8 ratio in CRs (r=-0.648, P=0.043). Plasma exosomes in abnormal group inhibited the co-expression of CD38HLA-DR+, an indicator of activation of CD8+ T cells, and the inhibitory effect was correlated with the CD4/CD8 ratio in CRs (r=0.478, P=0.039). Plasma exosomes in abnormal group inhibited the secretion of IFN-γ and IL-2 in CD8^+ T cells, and the inhibitory effect was significantly correlated with the CD4/CD8 ratio in CRs (r=0.654, P=0.002;r=0.700, P < 0.001). Plasma exosomes in abnormal group inhibited the proliferation of CD8^+ T cells, and there was a significant correlation between the inhibitory effect and the CD4/CD8 ratio in CRs (r=0.716, P<0.001). Conclusions Plasma exosomes from CD4/CD8 abnormal patients inhibites the activation, secretion and proliferation of CD8^+ T cells, suggesting that elevated exosomes in CRs with abnormal CD4/CD8 ratio has an inhibitory effect on over-activation and excessive inflammation in HIV patients.