Schweneker Marc, Favre David, Martin Jeffrey N, Deeks Steven G, McCune Joseph M
Division of Experimental Medicine, University of California, San Francisco, CA 94110, USA.
J Immunol. 2008 May 15;180(10):6490-500. doi: 10.4049/jimmunol.180.10.6490.
Infection with HIV usually results in chronic activation of the immune system, with profound quantitative and qualitative changes in the T cell compartment. To better understand the mechanistic basis for T cell dysfunction and to discern whether such mechanisms are reversed after effective antiviral treatment, we analyzed changes in signaling pathways of human CD4(+) and CD8(+) T cells from 57 HIV-infected subjects in varying stages of disease progression and treatment, including long-term nonprogressors, progressors, and chronically infected subjects provided effective antiretroviral therapy (responders). A previously described PhosFlow method was adapted and optimized so that protein phosphorylation could be visualized in phenotypically defined subpopulations of CD4(+) and CD8(+) T cells (naive, memory, and effector) by flow cytometry. T cell signaling induced by TCR cross-linking, IL-2, or PMA/ionomycin was found to be blunted within all T cell subpopulations in those with progressive HIV disease compared with long-term nonprogressors and responders. Although alterations in cellular signaling correlated with levels of basal phosphorylation, viral load, and/or expression of programmed death-1, it was the level of basal phosphorylation that appeared to be the factor most dominantly associated with impaired signaling. Notably, provision of effective antiretroviral therapy was associated with a normalization of both basal phosphorylation levels and T cell signaling. These data, in aggregate, suggest that generalized dysfunction of the T cell compartment during progressive HIV disease may be in part dependent upon an increased basal level of phosphorylation, which itself may be due to the heightened state of immune activation found in advanced disease.
感染HIV通常会导致免疫系统的慢性激活，T细胞区室在数量和质量上都会发生深刻变化。为了更好地理解T细胞功能障碍的机制基础，并确定这些机制在有效的抗病毒治疗后是否会逆转，我们分析了57名处于疾病进展和治疗不同阶段的HIV感染者（包括长期不进展者、进展者以及接受有效抗逆转录病毒治疗的慢性感染者（应答者））的人类CD4(+)和CD8(+) T细胞信号通路的变化。我们对先前描述的磷酸化流式细胞术方法进行了调整和优化，以便通过流式细胞术在CD4(+)和CD8(+) T细胞（初始、记忆和效应细胞）的表型定义亚群中可视化蛋白质磷酸化。与长期不进展者和应答者相比，在进展性HIV疾病患者的所有T细胞亚群中，TCR交联、IL-2或佛波酯/离子霉素诱导的T细胞信号均减弱。虽然细胞信号变化与基础磷酸化水平、病毒载量和/或程序性死亡-1的表达相关，但基础磷酸化水平似乎是与信号受损最主要相关的因素。值得注意的是，提供有效的抗逆转录病毒治疗与基础磷酸化水平和T细胞信号的正常化相关。总体而言，这些数据表明，进展性HIV疾病期间T细胞区室的普遍功能障碍可能部分取决于基础磷酸化水平的升高，而这本身可能是由于晚期疾病中免疫激活状态的增强。
