Not just a viral co-receptor: the role of CCR5 in HIV cure after allogeneic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only approach with confirmed cases of HIV cure. This review highlights the multifaceted role of CCR5 in this context, emphasizing that its impact extends far beyond functioning as a viral entry co-receptor, and outlines how donor and host CCR5 genotypes may influence reservoir depletion, transplant-related immune processes, and sustained remission.

Transplantation with CCR5Δ32/Δ32 donor cells is the most well documented approach to achieving HIV cure. However, growing evidence indicates that remission outcomes are shaped by multiple factors, including graft-versus-host-driven immune clearance and reservoir accessibility. Heterozygous CCR5Δ32 carriers are overrepresented among reported cases of HIV remission and may harbor smaller and more immunologically accessible reservoirs. Reduced or absent CCR5 expression alters lymphocyte migration and immune regulation, thereby modulating alloreactive responses including graft-versus-HIV-reservoir dynamics. Furthermore, cases of sustained remission without full CCR5 disruption demonstrate that immune-mediated mechanism can contribute to viral control independently of blocking viral entry.

CCR5 influences HIV remission after allo-HSCT through combined virological and immunological mechanisms. Understanding these CCR5-dependent mechanisms will be critical to refine transplant strategies and offers critical insight into mechanisms underlying HIV cure.