免疫无反应者 (INR) 是指尽管使用抗逆转录病毒疗法 (ART) 完全抑制病毒，但仍无法完全恢复 CD4 T 细胞计数的 HIV 感染者 (PLHIV)。 INR 导致非 HIV 相关发病率和死亡率的风险较高。先前的研究表明存在持续的定性缺陷。2000 年 HIV 研究（临床试验 NTC03994835）招募了 1895 名 PLHIV 患者，分为发现和验证队列。抑制性 ART ≥2 年后 CD4 T 细胞计数 <350 个细胞/mm3 的 PLHIV 被定义为 INR，并与 CD4 T 细胞计数 >500 个细胞/mm3 的免疫应答者 (IR) 进行比较。使用逻辑回归和基于排序的回归来分析临床数据、广泛的先天性和适应性免疫表型以及各种刺激后的离体单核细胞和淋巴细胞细胞因子的产生。发现队列由 62 INR 和 1224 IR 组成，验证队列由 26 INR 和 26 INR 组成。 243红外。 INR 年龄较大，在开始 ART 之前患有更晚期的 HIV 疾病，并且更频繁地有非艾滋病相关恶性肿瘤的病史。所有亚群中 INR 的 CD4 T 细胞绝对数量均较低。 CD4 T 细胞中激活的 (HLA-DR 、 CD38 ) 和耗尽的 (PD1 ) 亚群成比例增加。单核细胞和粒细胞免疫表型具有可比性。 INR淋巴细胞在刺激下产生较少的IL-22、IFN-γ、IL-10和IL-17。相反，单核细胞细胞因子的产生没有差异。 CD4 CD38 HLA-DR 和 CD4 PD1 亚群的比例与淋巴细胞细胞因子的产生呈负相关。与 IR 相比，INR 使 CD4 T 细胞过度激活并耗尽，并伴有淋巴细胞功能损伤，而先天免疫反应相当。我们的数据为考虑在 INR 中使用抗 PD1 疗法提供了依据。版权所有 © 2024 Vos, Navas, Meeder, Blaauw, Groenendijk, van Eekeren, Otten, Vadaq, Matzaraki, van Cranenbroek, Brinkman, van Lunzen, Joosten, Netea 、布洛克、范德文、科南和斯塔伦霍夫。

Immunological non-responders (INR) are people living with HIV (PLHIV) who fail to fully restore CD4+ T-cell counts despite complete viral suppression with antiretroviral therapy (ART). INR are at higher risk for non-HIV related morbidity and mortality. Previous research suggest persistent qualitative defects.The 2000HIV study (clinical trials NTC03994835) enrolled 1895 PLHIV, divided in a discovery and validation cohort. PLHIV with CD4 T-cell count <350 cells/mm3 after ≥2 years of suppressive ART were defined as INR and were compared to immunological responders (IR) with CD4 T-cell count >500 cells/mm3. Logistic and rank based regression were used to analyze clinical data, extensive innate and adaptive immunophenotyping, and ex vivo monocyte and lymphocyte cytokine production after stimulation with various stimuli.The discovery cohort consisted of 62 INR and 1224 IR, the validation cohort of 26 INR and 243 IR. INR were older, had more advanced HIV disease before starting ART and had more frequently a history of non-AIDS related malignancy. INR had lower absolute CD4+ T-cell numbers in all subsets. Activated (HLA-DR+, CD38+) and exhausted (PD1+) subpopulations were proportionally increased in CD4 T-cells. Monocyte and granulocyte immunophenotypes were comparable. INR lymphocytes produced less IL-22, IFN-γ, IL-10 and IL-17 to stimuli. In contrast, monocyte cytokine production did not differ. The proportions of CD4+CD38+HLA-DR+ and CD4+PD1+ subpopulations showed an inversed correlation to lymphocyte cytokine production.INR compared to IR have hyperactivated and exhausted CD4+ T-cells in combination with lymphocyte functional impairment, while innate immune responses were comparable. Our data provide a rationale to consider the use of anti-PD1 therapy in INR.Copyright © 2024 Vos, Navas, Meeder, Blaauw, Groenendijk, van Eekeren, Otten, Vadaq, Matzaraki, van Cranenbroek, Brinkman, van Lunzen, Joosten, Netea, Blok, van der Ven, Koenen and Stalenhoef.