Rutishauser Rachel Lena, Hartogensis Wendy, Deguit Christian Deo, Krone Melissa, Hoh Rebecca, Hecht Frederick M, Pilcher Christopher D, Bacchetti Peter, Deeks Steven G, Hunt Peter W, McCune Joseph M
1 Department of Medicine, University of California , San Francisco, San Francisco, California.
2 Department of Epidemiology and Biostatistics, University of California , San Francisco, San Francisco, California.
AIDS Res Hum Retroviruses. 2017 Jul;33(7):658-667. doi: 10.1089/AID.2016.0324. Epub 2017 Apr 25.
In untreated HIV infection, CD8 T cell exhaustion (i.e., decreased proliferative and effector capacity) is associated with high levels of expression of coinhibitory receptors, including PD-1, T cell immunoreceptor with Ig and ITIM domains (TIGIT), CD160, and 2B4. This is evident for both HIV-specific and non-HIV-specific CD8 T cells. Antiretroviral therapy (ART) initiated during chronic infection decreases but may not completely normalize the expression of such "exhaustion markers." Compared to initiation of ART later in the course of disease, initiation soon after infection reduces some parameters of chronic inflammation and adaptive immune dysfunction. However, it is not known if Early ART (e.g., initiated within the first 6 months after HIV infection) versus Delayed ART (e.g., initiated during chronic infection) preferentially reduces expression of exhaustion markers. We evaluated exhaustion marker expression on subsets of circulating effector and memory CD8 T cells at longitudinal pre- and post-ART (2 and 5 years on ART) time points from n = 19 (Early ART) and n = 23 (Delayed ART) individuals. Before ART, TIGIT and CD160 were expressed on a statistically significantly higher proportion of effector and transitional memory cells from individuals in the Delayed ART group: the timing of ART initiation, however, did not consistently affect the expression of the exhaustion markers once viral suppression was achieved. Understanding which factors do and do not regulate aspects of CD8 T cell exhaustion, including the expression of exhaustion markers, is critical to inform the rational design of CD8 T cell-based therapies to treat HIV, for which CD8 T cell exhaustion remains an important barrier to efficacy.
在未经治疗的HIV感染中，CD8 T细胞耗竭（即增殖和效应能力下降）与共抑制受体的高表达相关，这些共抑制受体包括程序性死亡受体1（PD-1）、具有免疫球蛋白和免疫酪氨酸抑制基序结构域的T细胞免疫受体（TIGIT）、CD160和2B4。这在HIV特异性和非HIV特异性CD8 T细胞中均很明显。慢性感染期间启动的抗逆转录病毒疗法（ART）可降低但可能无法使此类“耗竭标志物”的表达完全恢复正常。与疾病进程后期启动ART相比，感染后不久启动ART可降低慢性炎症和适应性免疫功能障碍的一些参数。然而，尚不清楚早期ART（例如，在HIV感染后的前6个月内启动）与延迟ART（例如，在慢性感染期间启动）是否能优先降低耗竭标志物的表达。我们在ART治疗前和治疗后（ART治疗2年和5年）的纵向时间点，评估了n = 19例（早期ART）和n = 23例（延迟ART）个体循环效应和记忆CD8 T细胞亚群上耗竭标志物的表达。在ART治疗前，延迟ART组个体的效应细胞和过渡性记忆细胞中，TIGIT和CD160的表达比例在统计学上显著更高：然而，一旦实现病毒抑制，ART启动时间并未始终影响耗竭标志物的表达。了解哪些因素能调节以及哪些因素不能调节CD8 T细胞耗竭的各个方面，包括耗竭标志物的表达，对于指导基于CD8 T细胞的HIV治疗方案的合理设计至关重要，因为CD8 T细胞耗竭仍然是影响治疗效果的重要障碍。
