Single-cell multiomics reveals persistence of HIV-1 in expanded cytotoxic T cell clones

• Published in: Immunity (Cambridge, Mass.) Mass.), 2022-06, Vol.55 (6), p.1013-1031.e7
• Main Authors: Collora, Jack A., Liu, Runxia, Pinto-Santini, Delia, Ravindra, Neal, Ganoza, Carmela, Lama, Javier R., Alfaro, Ricardo, Chiarella, Jennifer, Spudich, Serena, Mounzer, Karam, Tebas, Pablo, Montaner, Luis J., van Dijk, David, Duerr, Ann, Ho, Ya-Chi
• Format: Article
• Language: English
• Subjects: antigen stimulation; CD4-Positive T-Lymphocytes; clonal expansion; Clone Cells; cytotoxic CD4+ T lymphocytes; granzyme B; HIV Infections; HIV-1; HIV-1 latent reservoir; HIV-1 persistence; HIV-1-induced immune dysfunction; Humans; RNA; single-cell RNA-seq; T cell expansion dynamics; TNF response; Viremia
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2022.03.004

Understanding the drivers and markers of clonally expanding HIV-1-infected CD4+ T cells is essential for HIV-1 eradication. We used single-cell ECCITE-seq, which captures surface protein expression, cellular transcriptome, HIV-1 RNA, and TCR sequences within the same single cell to track clonal expansion dynamics in longitudinally archived samples from six HIV-1-infected individuals (during viremia and after suppressive antiretroviral therapy) and two uninfected individuals, in unstimulated conditions and after CMV and HIV-1 antigen stimulation. Despite antiretroviral therapy, persistent antigen and TNF responses shaped T cell clonal expansion. HIV-1 resided in Th1-polarized, antigen-responding T cells expressing BCL2 and SERPINB9 that may resist cell death. HIV-1 RNA+ T cell clones were larger in clone size, established during viremia, persistent after viral suppression, and enriched in GZMB+ cytotoxic effector memory Th1 cells. Targeting HIV-1-infected cytotoxic CD4+ T cells and drivers of clonal expansion provides another direction for HIV-1 eradication. [Display omitted] •Most HIV-1 RNA+ T cell clones are large, stable, GZMB+ cytotoxic effector memory Th1s•Some HIV-1 RNA+ cells express SERPINB9 and may be shielded from CD8+ T cell killing•Antigen stimulation, TNF, and cytotoxic T cell responses determine T cell clone size•Early ART cannot fully reduce chronic immune activation, and TNF responses persist Using single-cell ECCITE-seq, Collora et al. profiled 267 HIV-1 RNA+ cells and 68 expanded HIV-1 RNA+ T cell clones from 215,458 CD4+ T cells. HIV-1 resides in GZMB+ cytotoxic Th1 effector memory CD4+ T cell clones that are large and persistent. HIV-1-infected cytotoxic CD4+ T cells may evade cytotoxic CD8+ T cell killing through Seprin B9 degradation of granzyme B.