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

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.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2022 Hu, Li, Zhen, Wang, Huang, Zou, Zheng, Huang, Meng, Jin, Li, Zhou, Fu, Zhang, Li, Yang, Wang, Yang, Song, Fan, Jiao, Xu, Zhang, Zhou, Yuan, Huang, Qin, Wu, Shi, Wang and Zhang.)