CCL5-Secreting Virtual Memory CD8+ T Cells Inversely Associate With Viral Reservoir Size in HIV‐1−Infected Individuals on Antiretroviral Therapy
Wei Hu, Yanjun Li, Cheng Zhen, You-Yuan Wang, Hui-Huang Huang, Jun Zou, Yanqing Zheng, Gui-Chan Huang, Si-Run Meng, Jiehua Jin, Jing Li, Ming‐Ju Zhou, Yulong Fu, Peng Zhang, Xiaoyu Li, Tao Yang, Xiuwen Wang, Xiuhan Yang, Jin‐Wen Song, Xing Fan, Yan‐Mei Jiao, Ruonan Xu, Jiyuan Zhang, Chun‐Bao Zhou, Jin‐Hong Yuan, Lei Huang, Yaqin Qin, Fengyao Wu, Ming Shi, Fu‐Sheng Wang, Chao Zhang
Abstract
Recent studies highlighted that CD8+ T cells are necessary for restraining reservoir in HIV-1-infected individuals who undergo antiretroviral therapy (ART), whereas the underlying cellular and molecular mechanisms remain largely unknown. Here, we enrolled 60 virologically suppressed HIV-1-infected individuals, to assess the correlations of the effector molecules and phenotypic subsets of CD8+ T cells with HIV-1 DNA and cell-associated unspliced RNA (CA usRNA). We found that the levels of HIV-1 DNA and usRNA correlated positively with the percentage of CCL4+CCL5- CD8+ central memory cells (T CM ) while negatively with CCL4-CCL5+ CD8+ terminally differentiated effector memory cells (T EMRA ). Moreover, a virtual memory CD8+ T cell (T VM ) subset was enriched in CCL4-CCL5+ T EMRA cells and phenotypically distinctive from CCL4+ T CM subset, supported by single-cell RNA-Seq data. Specifically, T VM cells showed superior cytotoxicity potentially driven by T-bet and RUNX3, while CCL4+ T CM subset displayed a suppressive phenotype dominated by JUNB and CREM. In viral inhibition assays, T VM cells inhibited HIV-1 reactivation more effectively than non-T VM CD8+ T cells, which was dependent on CCL5 secretion. Our study highlights CCL5-secreting T VM cells subset as a potential determinant of HIV-1 reservoir size. This might be helpful to design CD8+ T cell-based therapeutic strategies for cure of the disease.