Background
Mechanisms underlying lasting HIV control in a subset of individuals with following analytical treatment interruption (ATI) remain undefined. We and others have shown that durable HIV control is associated with stem-like CD8 T cells that promote long-lived polyfunctional effector populations. Ex vivo disruption of CCR5 in autologous T cells led to partial post-ATI control in the Sangamo SB-728-1101 cohort. Patient 01-060 maintained virologic suppression for over five years following ATI. We examined the role of stemness and polyfunctional HIV specific T cells in mediating virus control, since durable HIV control is associated with stem-like CD8 T cells promoting lasting polyfunctional effector populations.
Methods
Flow cytometry and sc-RNAseq were used to assess in PBMCs stemness and HIV-specific polyfunctionality in post-treatment responders (n=5) and non-responders (n=4) of participants of the SB-728-1101 trial. Longitudinal enrichment patterns were compared with those in elite controllers (ECs).
Results
We observed increased frequencies of CD45ROhigh and CD45RAposCD45ROpos (RORA) CD8 T cells in responders. These subsets were enriched in patient 01-060 and were maintained for up to five years post-treatment, as measured by flow cytometry and single-cell RNA-seq. RORA population expressed TCF1 and displayed a stem-like transcriptional profile (high TCF7, CCR7, IL7R, and LEF1). Sustained control in participant 01-060 was marked by higher levels of TCF-1and Ki67 within RORA memory stem cell and polyfunctional T cells in later timepoints. scRNA seq confirmed that donor 01-060 uniquely maintained this stemness profile in TSCM and TEM and as well showed sustained frequencies of polyfunctional effector CD8 T cells over five years, supporting a lineage relationship in which stem-like precursors replenish durable effector populations. Compared to non-responders, responders had higher and persistent frequencies of HIV-specific INFg+/TNFa+ CD8 T cells, of KI67 proliferating cells and higher expression of TCF1 within HIV-specific CD8 T cells. The transcriptional profile of these CD8 T cells overlapped with HIV-specific EC CD8 T cells.
Conclusions
CD8 T cell with stem-like potential are consistent correlates of HIV control. They might prove to have prognostic value as a biomarker in HIV cure studies. They might also be an effective therapeutic target. CCR5 disruption of memory stem cells (using either ex vivo or in vivo editing) might prove to be an effective strategy.