Chew Glen M, Padua Ana Joy P, Chow Dominic C, Souza Scott A, Clements Danielle M, Corley Michael J, Pang Alina P S, Alejandria Marissa M, Gerschenson Mariana, Shikuma Cecilia M, Ndhlovu Lishomwa C
John A. Burns School of Medicine, University of Hawai'i, Honolulu, Hawaii, USA.
College of Medicine, University of the Philippines, Manila, Philippines.
AIDS Res Hum Retroviruses. 2021 Jan;37(1):24-33. doi: 10.1089/AID.2020.0172. Epub 2020 Nov 5.
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. polyfunctional HIV-Gag-specific CD8 T cell responses to anti-PD-L1 mAb significantly improved ( < .05) over the 8-week course of metformin therapy. Moreover, frequencies of both intermediate (CD14CD16; = 0.89, = .01) and nonclassical (CD14CD16; = 0.92, = .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.
靶向抑制性免疫检查点受体通路在改善抗癌T细胞反应以消除肿瘤方面已取得显著成功。此类免疫治疗策略正被用于实现HIV缓解。二甲双胍在增强程序性细胞死亡蛋白1（PD-1）阻断的疗效和恢复抗肿瘤T细胞免疫方面已显示出良好的临床效果。此外，已知单核细胞是抗PD-1免疫治疗无进展生存期的有力预测指标。在一项单臂临床试验中，我们评估了7名血糖正常、病毒得到抑制且接受联合抗逆转录病毒疗法（cART）的HIV感染者在接受为期8周的二甲双胍治疗过程中的免疫效应。我们使用流式细胞术评估了外周血中HIV-Gag特异性T细胞对免疫检查点阻断（ICB）（使用抗PD-L1和抗含免疫球蛋白和ITIM结构域的T细胞免疫受体（TIGIT）单克隆抗体（mAb））的反应变化，以及CD8 T细胞和单核细胞亚群的变化。研究参与者均为男性，71%（5/7）为白种人，中位年龄61岁，CD4细胞计数为739个/μL，在稳定的cART治疗1年以上时血浆HIV RNA<50拷贝/mL。在为期8周的二甲双胍治疗过程中，对抗PD-L1 mAb的多功能HIV-Gag特异性CD8 T细胞反应显著改善（P<0.05）。此外，入组时中间型（CD14+CD16+；r=0.89，P=0.01）和非经典型（CD14-CD16+；r=0.92，P=0.01）单核细胞的频率可预测抗HIV CD8 T细胞对PD-L1阻断反应的强度。总体而言，这些发现突出表明，为期8周的二甲双胍疗程可增加CD8 T细胞的多功能性，且基线单核细胞亚群频率可能是PD-L1阻断疗效的潜在决定因素。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。
