I Divisione Malattie Infettive, H.L. Sacco, Milan, Italy.
Blood. 2011 Sep 22;118(12):3263-72. doi: 10.1182/blood-2011-01-329060. Epub 2011 May 16.
Despite optimal suppression of HIV replication, restoration of CD4(+) T cells is not always achieved in antiretroviral therapy-treated individuals. Defective CD4 recovery in immunologic nonresponders is possibly associated with TLR-mediated immune activation driven by alterations of gut permeability. Hydroxychloroquine (HCQ) reduces endosomal TLR signaling; thus, we verified whether HCQ could dampen immune activation and be associated with an increase in CD4(+) T cells. To this end, we enrolled in a prospective study 20 HIV-infected immunologic nonresponders (CD4 count < 200 cells/mL or CD4 increase < 5% in the last 12 months) who received 400 mg/day HCQ for 6 months. HCQ had a notable impact on immune activation as shown by significant modifications of the following parameters: (1) reduced plasma lipopolysaccharide; (2) decreased TLR4-expressing CD14(+) cells, TLR4-mediated signal transduction, and mRNA synthesis; (3) reduced percentages of activated CD4(+) (CD4(+)/Ki67(+)) and CD14(+) (CD14(+)/CD69(+)) cells; (4) increased T-regulatory cells (Tregs), naive Tregs, and TLR4-expressing Tregs; (5) augmented plasmacytoid dendritic cells and reduced IFNα-secreting plasmacytoid dendritic cells; and (6) reduced IL-6 and TNFα production. HCQ-induced immune modulation was associated with increased percentages of circulating CD4(+) T cells and was mostly retained 2 months after therapy interruption. HCQ reduces lipopolysaccharide/TLR-mediated immune activation; this compound could be a useful immunomodulant in HIV-infected patients. This study is registered at EutraCT as 2009-012499-28 with study number HLS01/2009-1-16-03-2009.
尽管抗逆转录病毒治疗能最大限度地抑制 HIV 复制，但在接受治疗的个体中，CD4(+)T 细胞的恢复并不总是能实现。免疫无应答者的 CD4 恢复缺陷可能与 TLR 介导的免疫激活有关，这种激活是由肠道通透性改变驱动的。羟氯喹（HCQ）可降低内体 TLR 信号；因此，我们验证了 HCQ 是否能抑制免疫激活，并与 CD4(+)T 细胞的增加相关。为此，我们前瞻性地纳入了 20 名 HIV 感染免疫无应答者（CD4 计数<200 个/毫升或在过去 12 个月内 CD4 增加<5%），他们接受了 400mg/天的 HCQ 治疗，为期 6 个月。HCQ 对免疫激活有显著影响，表现在以下参数的显著改变：（1）降低血浆脂多糖；（2）减少 TLR4 表达的 CD14(+)细胞、TLR4 介导的信号转导和 mRNA 合成；（3）减少激活的 CD4(+)（CD4(+)/Ki67(+））和 CD14(+)（CD14(+)/CD69(+））细胞的比例；（4）增加 T 调节细胞（Tregs）、幼稚 Tregs 和 TLR4 表达的 Tregs；（5）增加浆细胞样树突状细胞，减少 IFNα 分泌的浆细胞样树突状细胞；（6）减少 IL-6 和 TNFα 的产生。HCQ 诱导的免疫调节与循环 CD4(+)T 细胞比例的增加有关，在停药后 2 个月仍能保留。HCQ 降低了脂多糖/TLR 介导的免疫激活；这种化合物可能是 HIV 感染患者有用的免疫调节剂。本研究在 EutraCT 注册，编号为 2009-012499-28，注册号为 HLS01/2009-1-16-03-2009。
