Emerging CCR5-Based Therapeutic Potential of JAK/STAT Inhibitors and CCR5Δ32 Hematopoietic Stem Cell Transplantation.

C-C chemokine receptor type 5 (CCR5) is the primary co-receptor mediating the entry of R5-tropic human immunodeficiency virus type 1 (HIV-1) into CD4+ T cells and macrophages, making it one of the most promising therapeutic targets in HIV cure research. The naturally occurring CCR5Δ32 mutation which abolishes surface CCR5 expression in homozygous individuals has provided strong clinical evidence for CCR5-directed strategies after multiple cases of sustained HIV remission following allogeneic hematopoietic stem cell transplantation (HSCT) from CCR5Δ32 donors. This review summarizes the current understanding of the evolutionary origin and global distribution of the CCR5Δ32 allele, as well as the clinical evidence from landmark transplantation cases. We also discuss recent findings demonstrating that durable HIV remission may be achieved following transplantation from heterozygous CCR5 wild-type/Δ32 donors, suggesting that factors such as donor chimerism, conditioning regimens and graft-versus-reservoir effects contribute substantially to reservoir clearance alongside CCR5 disruption. In addition, we examine emerging evidence that pharmacological inhibition of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway can reversibly suppress CCR5 expression, reduce HIV replication, limit reservoir establishment, and attenuate immune activation. Collectively, these advances highlight the evolving landscape of CCR5-targeted therapies and support the development of safer and more broadly applicable approaches toward durable HIV remission and, ultimately, an HIV cure.