Premeaux Thomas A, Moser Carlee B, McKhann Ashley, Hoenigl Martin, Yeung Stephen T, Pang Alina P S, Corley Michael J, Lederman Michael M, Landay Alan L, Gianella Sara, Ndhlovu Lishomwa C
Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
Center for Biostatistics in AIDS Research in the Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
Open Forum Infect Dis. 2022 Jan 21;9(3):ofab570. doi: 10.1093/ofid/ofab570. eCollection 2022 Mar.
Although cell surface immune checkpoint proteins (ICPs) such as PD-1 expressed on T cells are associated with T-cell exhaustion, HIV disease progression, and AIDS events, they have shown limited utility in predicting non-AIDS morbidity. Given that ICPs also exist in soluble forms and are elevated in ART-treated HIV infection, we tested the hypothesis that soluble ICPs may be predictive of non-AIDS events in adults initiating ART.
Utilizing a nested case-control study from the AIDS Clinical Trials Group ALLRT cohort, we measured plasma levels of 15 soluble inhibitory and activating ICPs by Luminex. Participants (134 cases, 292 matched controls) were evaluated pre-ART, a year post-ART, and immediately preceding a non-AIDS event, which included myocardial infarction (MI)/stroke, malignancy, serious bacterial infection, and nonaccidental death.
Conditional logistic regression analysis determined that higher levels of soluble CD27 were associated with increased risk of non-AIDS events at all time points. Higher levels of CD40 at baseline and pre-event and CD80 at pre-event were associated with increased risk of non-AIDS events. Examining specific non-AIDS events, multiple ICPs were associated with malignancy at baseline and pre-event, whereas only higher CD27 levels were associated with increased risk of MI/stroke at year 1 and pre-event.
While select soluble ICPs were associated with non-AIDS events, CD27 emerged as a consistent marker irrespective of ART. Our data may offer guidance on new targets for early clinical monitoring in people with HIV who remain at greater risk of specific non-AIDS events.
尽管T细胞表面表达的免疫检查点蛋白（ICP）如PD-1与T细胞耗竭、HIV疾病进展和艾滋病事件相关，但它们在预测非艾滋病发病率方面的效用有限。鉴于ICP也以可溶性形式存在且在接受抗逆转录病毒治疗（ART）的HIV感染中升高，我们检验了可溶性ICP可能预测开始接受ART的成年人非艾滋病事件的假设。
利用艾滋病临床试验组ALLRT队列的一项巢式病例对照研究，我们通过Luminex测定了15种可溶性抑制性和激活性ICP的血浆水平。参与者（134例病例，292例匹配对照）在ART治疗前、ART治疗后一年以及非艾滋病事件（包括心肌梗死/中风、恶性肿瘤、严重细菌感染和非意外死亡）即将发生前接受评估。
条件逻辑回归分析确定，在所有时间点，可溶性CD27水平较高与非艾滋病事件风险增加相关。基线和事件前CD40水平较高以及事件前CD80水平较高与非艾滋病事件风险增加相关。在检查特定的非艾滋病事件时，多种ICP在基线和事件前与恶性肿瘤相关，而只有较高的CD27水平在第1年和事件前与心肌梗死/中风风险增加相关。
虽然某些可溶性ICP与非艾滋病事件相关，但无论ART情况如何，CD27都是一个一致的标志物。我们的数据可能为仍面临特定非艾滋病事件更高风险的HIV感染者早期临床监测的新靶点提供指导。
