1Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
School of Medicine, University of Texas Medical Branch, Galveston, Texas, USA.
mBio. 2024 Oct 16;15(10):e0226524. doi: 10.1128/mbio.02265-24. Epub 2024 Sep 17.
Despite the success in the management of HIV with antiretroviral therapy (ART), people with HIV (PWH) have a heightened state of immune activation and inflammation, and an estimated 10%-40% demonstrate poor CD4 T-cell reconstitution, thereby increasing their mortality and morbidity risk burden. Soluble immunoregulatory proteins that function in lymphocyte activation or inhibition are elevated in PWH and associate with T-cell dysfunction, HIV persistence, and are predictive of comorbid outcomes. Here, we measured a panel of 35 circulating immunoregulatory proteins in 116 PWH with variations in CD4 T-cell counts (poor CD4 trajectory: <200 cells/μl, = 34 or immune competent: CD4 >500 cells/μl, = 82) by Luminex. Participants were enrolled in the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials cohort, had initiated ART on enrollment, and had been on suppressive ART for 1 year. Using non-parametric analysis, we found that the levels of CD276, ICOSL, BAFF, OX40, galectin-1, and galectin-9 were significantly higher in PWH with poor CD4 trajectories compared to individuals with immune-competent CD4 T-cell count. Notably, in logistic models, ICOSL and OX40 remained significant after adjusting for age and baseline plasma HIV RNA. Furthermore, Extreme Gradient Boosting machine learning models comprising co-stimulatory and inhibitory checkpoint proteins yielded high accuracy in classification of individuals with poor CD4 trajectories. In summary, we identified a novel signature of circulating immunoregulatory proteins indicative of poor CD4 trajectories that may serve as potential targets to monitor and manage immune perturbations more accurately in PWH during suppressive ART.
It is essential to track immune perturbations related to insufficient CD4 T-cell recovery in PWH on suppressive ART as those with incomplete reconstitution are at a greater risk of non-AIDS-related morbidity and mortality. Several inflammatory soluble mediators have associated with poor immune reconstitution and adverse morbid outcomes in PWH, yet their implementation into routine clinical care to guide management remains inconsistent. Circulating immune checkpoint proteins have been linked to dysregulated immune pathways during suppressive ART and may serve as improved surrogate markers of clinical relevance. Here we investigate soluble lymphocyte-associated immunoregulatory proteins in virally suppressed PWH with no reported co-morbid outcomes and varying CD4 T-cell counts, to reveal underlying pathways that remain perturbed despite ART. This novel signature of immunoregulatory markers pertaining to poor CD4 T-cell trajectories uncover previously overlooked immune checkpoints as important targets for clinical monitoring of PWH in the setting of durable viral suppression by ART.
尽管抗逆转录病毒疗法 (ART) 在 HIV 管理方面取得了成功，但 HIV 感染者 (PWH) 仍处于免疫激活和炎症的高度状态，估计有 10%-40%的人表现出 CD4 T 细胞重建不良，从而增加了他们的死亡率和发病率风险负担。在 PWH 中，具有淋巴细胞激活或抑制作用的可溶性免疫调节蛋白升高，并与 T 细胞功能障碍、HIV 持续存在相关，并且是合并症结局的预测因子。在这里，我们通过 Luminex 测量了 116 名 CD4 T 细胞计数存在差异的 PWH（CD4 轨迹不良：<200 个/μl，n=34 或免疫功能正常：CD4>500 个/μl，n=82）中 35 种循环免疫调节蛋白的水平。参与者被纳入 AIDS 临床试验组纵向关联随机试验队列，在入组时开始接受 ART，并在接受抑制性 ART 治疗 1 年后。使用非参数分析，我们发现与免疫功能正常的 CD4 T 细胞计数相比，CD4 轨迹不良的 PWH 的 CD276、ICOSL、BAFF、OX40、半乳糖凝集素-1 和半乳糖凝集素-9 水平显着升高。值得注意的是，在调整年龄和基线血浆 HIV RNA 后，ICOSL 和 OX40 在逻辑模型中仍然显着。此外，由共刺激和抑制性检查点蛋白组成的极端梯度提升机器学习模型在分类 CD4 轨迹不良的个体方面具有很高的准确性。总之，我们确定了一种新型循环免疫调节蛋白特征，表明 CD4 轨迹不良，这可能成为监测和更准确地管理接受抑制性 ART 的 PWH 免疫失调的潜在目标。
在接受抑制性 ART 的 PWH 中，追踪与 CD4 T 细胞恢复不完全相关的免疫失调至关重要，因为那些重建不完全的人患非 AIDS 相关发病率和死亡率的风险更高。一些炎症性可溶性介质与 PWH 中的免疫重建不良和不良的发病结局相关，但将其纳入常规临床护理以指导管理的实施仍不一致。循环免疫检查点蛋白与抑制性 ART 期间失调的免疫途径有关，可能是改善临床相关性的替代标志物。在这里，我们研究了病毒抑制的 PWH 中的可溶性淋巴细胞相关免疫调节蛋白，这些 PWH 没有报告合并症结局且 CD4 T 细胞计数不同，以揭示尽管接受 ART 但仍存在的潜在途径。与 CD4 T 细胞轨迹不良相关的新型免疫调节标志物特征揭示了以前被忽视的免疫检查点作为重要的临床监测靶点，用于在 ART 持久抑制病毒的情况下监测 PWH。
