Unidade de Imunologia Clínica, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Clínica de Doenças Infecciosas, Hospital de Santa Maria, Lisboa, Portugal.
AIDS. 2012 Jun 1;26(9):1065-71. doi: 10.1097/QAD.0b013e32835374db.
Hyper-immune activation is a main determinant of HIV disease progression, potentially counter-acted by T-cell inhibitory pathways. Here we investigated, for the first time, inhibitory molecules in HIV-2 infection, a naturally occurring attenuated form of HIV disease, associated with reduced viremia and very slow rates of CD4 T-cell decline.
Programmed death (PD)-1/PD-L1, an important pathway in limiting immunopathology, and its possible relationship with T-cell immunoglobulin and mucin-domain containing molecule-3 (TIM-3), a recently identified inhibitory molecule, were studied in untreated HIV-2 and HIV-1 cohorts, matched for degree of CD4 T-cell depletion, and noninfected individuals.
Flow cytometric analysis of T-cell expression of PD-1, PD-L1 and TIM-3, combined with markers of cell differentiation, activation, cycling and survival. Statistical analysis was performed using ANOVA, Mann-Whitney/Wilcoxon tests, Spearman's correlations, multiple linear regressions and canonical correlation analysis.
T-cell expression of PD-1 and PD-L1 was tightly associated and directly correlated with CD4 T-cell depletion and immune activation in HIV-2 infection. No such correlation was found for PD-L1 expression in HIV-1-positive patients. Central memory and intermediate memory cells, rather than terminally differentiated T-cells, expressed the highest levels of both PD-1 and PD-L1 molecules. Conversely, TIM-3 expression was independent of T-cell differentiation and dissociated from cell cycling, suggesting distinct induction mechanisms. Importantly, in contrast with HIV-1, no significant increases in TIM-3 expression were found in the HIV-2 cohort.
Our data suggest that PD-1/PD-L1 molecules, rather than markers of T-cell exhaustion, may act as modulators of T-cell immune activation, contributing to the slower course of HIV-2 infection. These data have implications for the design of antiretroviral therapy-complementary immune-based strategies.
超免疫激活是 HIV 疾病进展的主要决定因素，可能会被 T 细胞抑制途径所拮抗。在这里，我们首次研究了 HIV-2 感染中的抑制分子，HIV-2 是一种天然存在的 HIV 疾病减毒株，与病毒载量降低和 CD4 T 细胞下降速度非常缓慢有关。
程序性死亡（PD）-1/PD-L1 是限制免疫病理的重要途径，及其与最近发现的抑制分子 T 细胞免疫球蛋白和粘蛋白结构域包含分子 3（TIM-3）的可能关系，在未经治疗的 HIV-2 和 HIV-1 队列中进行了研究，这些队列与 CD4 T 细胞耗竭程度相匹配，并且与未感染个体相匹配。
使用流式细胞术分析 PD-1、PD-L1 和 TIM-3 在 T 细胞上的表达，同时结合细胞分化、激活、细胞周期和存活的标志物进行分析。使用方差分析、Mann-Whitney/Wilcoxon 检验、Spearman 相关分析、多元线性回归和典型相关分析进行统计分析。
在 HIV-2 感染中，PD-1 和 PD-L1 的 T 细胞表达与 CD4 T 细胞耗竭和免疫激活密切相关，并呈直接相关。在 HIV-1 阳性患者中，未发现 PD-L1 表达存在这种相关性。中央记忆和中间记忆细胞而不是终末分化的 T 细胞表达了最高水平的 PD-1 和 PD-L1 分子。相反，TIM-3 的表达与 T 细胞分化无关，与细胞周期分离，提示存在不同的诱导机制。重要的是，与 HIV-1 不同，在 HIV-2 队列中未发现 TIM-3 表达的显著增加。
我们的数据表明，PD-1/PD-L1 分子而不是 T 细胞耗竭的标志物，可能作为 T 细胞免疫激活的调节剂，导致 HIV-2 感染的进程较慢。这些数据对设计抗逆转录病毒治疗互补的免疫策略具有重要意义。
