AUTHOR=Hu Wei , Li Yan-Jun , Zhen Cheng , Wang You-Yuan , Huang Hui-Huang , Zou Jun , Zheng Yan-Qing , Huang Gui-Chan , Meng Si-Run , Jin Jie-Hua , Li Jing , Zhou Ming-Ju , Fu Yu-Long , Zhang Peng , Li Xiao-Yu , Yang Tao , Wang Xiu-Wen , Yang Xiu-Han , Song Jin-Wen , Fan Xing , Jiao Yan-Mei , Xu Ruo-Nan , Zhang Ji-Yuan , Zhou Chun-Bao , Yuan Jin-Hong , Huang Lei , Qin Ya-Qin , Wu Feng-Yao , Shi Ming , Wang Fu-Sheng , Zhang Chao 

TITLE=CCL5-Secreting Virtual Memory CD8+ T Cells Inversely Associate With Viral Reservoir Size in HIV‐1−Infected Individuals on Antiretroviral Therapy

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.897569

DOI=10.3389/fimmu.2022.897569

ISSN=1664-3224

ABSTRACT=<p>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<sub>CM</sub>) while negatively with CCL4-CCL5+ CD8+ terminally differentiated effector memory cells (T<sub>EMRA</sub>). Moreover, a virtual memory CD8+ T cell (T<sub>VM</sub>) subset was enriched in CCL4-CCL5+ T<sub>EMRA</sub> cells and phenotypically distinctive from CCL4+ T<sub>CM</sub> subset, supported by single-cell RNA-Seq data. Specifically, T<sub>VM</sub> cells showed superior cytotoxicity potentially driven by T-bet and RUNX3, while CCL4+ T<sub>CM</sub> subset displayed a suppressive phenotype dominated by JUNB and CREM. In viral inhibition assays, T<sub>VM</sub> cells inhibited HIV-1 reactivation more effectively than non-T<sub>VM</sub> CD8+ T cells, which was dependent on CCL5 secretion. Our study highlights CCL5-secreting T<sub>VM</sub> 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.</p>