Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR.
J Immunol. 2022 Jan 1;208(1):54-62. doi: 10.4049/jimmunol.2100367. Epub 2021 Dec 1.
In people with HIV (PWH) on antiretroviral therapy (ART), immune dysfunction persists, including elevated expression of immune checkpoint (IC) proteins on total and HIV-specific T cells. Reversing immune exhaustion is one strategy to enhance the elimination of HIV-infected cells that persist in PWH on ART. We aimed to evaluate whether blocking CTL-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), T cell Ig domain and mucin domain 3 (TIM-3), T cell Ig and ITIM domain (TIGIT) and lymphocyte activation gene-3 (LAG-3) alone or in combination would enhance HIV-specific CD4 and CD8 T cell function ex vivo. Intracellular cytokine staining was performed using human PBMCs from PWH on ART ( = 11) and expression of CD107a, IFN-γ, TNF-α, and IL-2 was quantified with HIV peptides and Abs to IC. We found the following: 1) IC blockade enhanced the induction of CD107a and IL-2 but not IFN-γ and TNF-α in response to Gag and Nef peptides; 2) the induction of CD107a and IL-2 was greatest with multiple combinations of two Abs; and 3) Abs to LAG-3, CTLA-4, and TIGIT in combinations showed synergistic induction of IL-2 in HIV-specific CD8 and CD107a and IL-2 production in HIV-specific CD4 and CD8 T cells. These results demonstrate that the combination of Abs to LAG-3, CTLA-4, or TIGIT can increase the frequency of cells expressing CD107a and IL-2 that associated with cytotoxicity and survival of HIV-specific CD4 and CD8 T cells in PWH on ART. These combinations should be further explored for an HIV cure.
在接受抗逆转录病毒疗法（ART）的艾滋病毒（HIV）感染者（PWH）中，免疫功能仍然存在障碍，包括总 T 细胞和 HIV 特异性 T 细胞上免疫检查点（IC）蛋白的表达升高。逆转免疫衰竭是增强清除 ART 中持续存在的 HIV 感染细胞的策略之一。我们旨在评估单独或联合阻断 CTLA-4、程序性细胞死亡蛋白 1（PD-1）、T 细胞免疫球蛋白和粘蛋白域 3（TIM-3）、T 细胞免疫球蛋白和 ITIM 域（TIGIT）和淋巴细胞激活基因-3（LAG-3）是否会增强 HIV 特异性 CD4 和 CD8 T 细胞的体外功能。使用来自接受 ART 的 PWH（n = 11）的人外周血单核细胞（PBMC）进行细胞内细胞因子染色，并使用 HIV 肽和 IC 抗体定量测定 CD107a、IFN-γ、TNF-α和 IL-2 的表达。我们发现：1）IC 阻断增强了对 Gag 和 Nef 肽的反应中 CD107a 和 IL-2 的诱导，但不能诱导 IFN-γ和 TNF-α的诱导；2）两种抗体的多种组合诱导 CD107a 和 IL-2 的效果最大；3）LAG-3、CTLA-4 和 TIGIT 的 Abs 组合协同诱导 HIV 特异性 CD8 和 CD107a 的 IL-2，以及 HIV 特异性 CD4 和 CD8 T 细胞中 IL-2 的产生。这些结果表明，LAG-3、CTLA-4 或 TIGIT 的 Abs 组合可以增加表达 CD107a 和 IL-2 的细胞的频率，这些细胞与 ART 中 HIV 特异性 CD4 和 CD8 T 细胞的细胞毒性和存活相关。这些组合应进一步探索用于 HIV 治愈。
