Targeting inhibitory immune checkpoint receptor pathways has shown remarkable success in improving anticancer T cell responses for the elimination of tumors. Such immunotherapeutic strategies are being pursued for HIV remission. Metformin has shown favorable clinical outcomes in enhancing the efficacy of programmed cell death-1 (PD-1) blockade and restoring antitumor T cell immunity. Furthermore, monocytes are known to be a strong predictor of progression-free survival in response to anti-PD-1 immunotherapy. In a single-arm clinical trial, we evaluated the immunological effects over an 8-week course of metformin therapy in seven euglycemic, virally suppressed HIV-infected participants on combination antiretroviral therapy (cART). We assessed changes in peripheral HIV-Gag-specific T cell responses to immune checkpoint blockade (ICB) with anti-PD-L1 and anti-T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) monoclonal antibodies (mAbs) and changes in CD8 T cell and monocyte subsets using flow cytometry. Study participants were all male, 71% (5/7) Caucasian, with a median age of 61 years, CD4 count of 739 cells/μL, and plasma HIV RNA of <50 copies/mL on stable cART for >1 year. Ex vivo polyfunctional HIV-Gag-specific CD8 T cell responses to anti-PD-L1 mAb significantly improved (p < .05) over the 8-week course of metformin therapy. Moreover, frequencies of both intermediate (CD14⁺CD16⁺; r = 0.89, p = .01) and nonclassical (CD14^lowCD16⁺; r = 0.92, p = .01) monocytes at entry were predictive of the magnitude of the anti-HIV CD8 T cell responses to PD-L1 blockade. Collectively, these findings highlight that 8-week course of metformin increases the polyfunctionality of CD8 T cells and that baseline monocyte subset frequencies may be a potential determinant of PD-L1 blockade efficacy. These data provide valuable information for HIV remission trials that utilize ICB strategies to enhance anti-HIV CD8 T cell immunity.

中文翻译：

---

在病毒学抑制的 HIV 感染成人中进行短暂的二甲双胍辅助治疗对多功能 HIV 特异性 CD8 T 细胞对 PD-L1 阻断反应的影响

靶向抑制性免疫检查点受体途径在改善抗癌 T 细胞反应以消除肿瘤方面已显示出显着的成功。正在寻求这种免疫治疗策略以缓解艾滋病毒。二甲双胍在增强程序性细胞死亡-1 (PD-1) 阻断和恢复抗肿瘤 T 细胞免疫方面显示出良好的临床效果。此外，已知单核细胞是响应抗 PD-1 免疫疗法的无进展生存期的强预测因子。在一项单臂临床试验中，我们评估了 8 周二甲双胍治疗对 7 名血糖正常、病毒抑制的 HIV 感染者联合抗逆转录病毒治疗 (cART) 的免疫效果。我们用抗 PD-L1 和用免疫球蛋白和 ITIM 结构域 (TIGIT) 单克隆抗体 (mAb) 的抗 T 细胞免疫受体评估了外周 HIV-Gag 特异性 T 细胞对免疫检查点阻断 (ICB) 反应的变化以及 CD8 T 的变化使用流式细胞仪检测细胞和单核细胞亚群。研究参与者均为男性，71% (5/7) 高加索人，中位年龄为 61 岁，CD4 计数为 739 个细胞/μL，血浆 HIV RNA <50 拷贝/mL，稳定 cART 超过 1 年。在为期 8 周的二甲双胍治疗过程中，离体多功能 HIV-Gag 特异性 CD8 T 细胞对抗 PD-L1 mAb 的反应显着改善 ( p  < .05)。此外，中间频率 (CD14 ⁺ CD16 ⁺ ; r  = 0.89, p  = .01) 和非经典频率 (CD14 ^low CD16 ⁺ ; r  = 0.92, p = .01) 进入时的单核细胞可预测抗 HIV CD8 T 细胞对 PD-L1 阻断的反应程度。总的来说，这些发现强调了 8 周的二甲双胍疗程增加了 CD8 T 细胞的多功能性，并且基线单核细胞亚群频率可能是 PD-L1 阻断效果的潜在决定因素。这些数据为利用 ICB 策略增强抗 HIV CD8 T 细胞免疫的 HIV 缓解试验提供了有价值的信息。