Africa Health Research Institute (AHRI), Durban, South Africa.
HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal (UKZN), Durban, South Africa.
J Acquir Immune Defic Syndr. 2019 Apr 15;80(5):596-604. doi: 10.1097/QAI.0000000000001946.
Systemic levels of interleukin (IL)-7 at antiretroviral therapy (ART) initiation have previously been shown to be predictive of HIV-linked paradoxical cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS). We therefore explored IL-7/IL-7 receptor (IL-7/IL-7R) signaling pathway dysfunction, with related alterations in immune function, as a mechanism underlying C-IRIS.
HIV-infected patients with cryptococcal meningitis who experienced C-IRIS (n = 27) were compared with CD4 T-cell count-matched counterparts without C-IRIS (n = 27), after antifungal therapy and pre-ART initiation. Flow cytometry was used to assess T-cell and monocyte phenotypes and functions.
Proportions of IL-7R+ CD4 or CD8 T cells correlated positively with CD4 T-cell counts and proportions of central memory and naive CD4 and CD8 T-cell pre-ART (all r > 0.50 and P < 0.05); however, the former negatively correlated with CD4 T-cell counts fold-increase on ART in non-C-IRIS but not C-IRIS patients. Higher frequencies of activated monocytes (CD14CD86 or CD14+HLA-DR+; P ≤ 0.038) were also observed in C-IRIS compared with non-C-IRIS patients, and those who failed to clear cryptococci from cerebrospinal fluid before ART had higher levels of activated monocytes (CD14+HLA-DR+, P = 0.017) compared with those who cleared. In multivariate regression, CD14+HLA-DR+ monocytes were independently associated with C-IRIS [hazard ratio = 1.055 (1.013-1.098); P = 0.009].
In contrast to non-C-IRIS patients, C-IRIS patients displayed a lack of association between proportions of IL-7R+ T cells and several markers of T-cell homeostasis. They also exhibited higher monocyte activation linked to cerebrospinal fluid cryptococcal culture positivity before ART. These data suggest a role for IL-7/IL-7R signaling pathway dysregulation in the pathogenesis of C-IRIS, possibly linked to monocyte activation and residual pathogen burden before ART.
在开始抗逆转录病毒治疗（ART）时，白细胞介素（IL）-7 的全身水平先前已被证明可预测 HIV 相关的隐球菌病相关免疫重建炎症综合征（C-IRIS）。因此，我们探讨了 IL-7/IL-7 受体（IL-7/IL-7R）信号通路功能障碍及其相关的免疫功能改变，作为 C-IRIS 发病机制的一种机制。
比较了抗真菌治疗和 ART 开始前经历 C-IRIS（n = 27）的 HIV 感染 cryptococcal 脑膜炎患者与无 C-IRIS（n = 27）的 CD4 T 细胞计数匹配的对照者。使用流式细胞术评估 T 细胞和单核细胞表型和功能。
IL-7R+CD4 或 CD8 T 细胞的比例与 CD4 T 细胞计数以及中央记忆和幼稚 CD4 和 CD8 T 细胞的比例呈正相关（所有 r > 0.50，P < 0.05）；然而，前者与非 C-IRIS 患者的 ART 上 CD4 T 细胞计数增加倍数呈负相关，但在 C-IRIS 患者中并非如此。与非 C-IRIS 患者相比，C-IRIS 患者的活化单核细胞（CD14CD86 或 CD14+HLA-DR+；P ≤ 0.038）的频率也更高，并且在 ART 之前未能从脑脊液中清除隐球菌的患者的活化单核细胞（CD14+HLA-DR+，P = 0.017）水平更高。在多变量回归中，CD14+HLA-DR+单核细胞与 C-IRIS 独立相关[危险比= 1.055（1.013-1.098）；P = 0.009]。
与非 C-IRIS 患者相比，C-IRIS 患者的 IL-7R+T 细胞比例与 T 细胞稳态的多个标志物之间缺乏关联。他们还表现出更高的单核细胞活化，与 ART 前脑脊液中隐球菌培养阳性相关。这些数据表明，IL-7/IL-7R 信号通路失调可能与单核细胞活化和 ART 前残留病原体负荷有关，在 C-IRIS 的发病机制中起作用。
