Hematopoietic Stem Cell-Based Therapy for HIV Disease: Prostaglandin-Modulated Transplantation

Abstract

Allogeneic stem cell transplantation of hematopoietic stem cells (HSCs) resistant to HIV-1 (CCR5 null cells) using a regimen to improve homing, engraftment, and preferential cord chimerism of umbilical cord blood (UCB) cells homozygous for CCR5∆32 mutation (UCBΔ32/Δ32) favors utilization of prostaglandin E 2 (PGE 2)-mediated mechanisms to facilitate allogeneic transplantation. Since PGE 2 has additional capacity to down-regulate CCR5 expression, this could enable dual effect a) Allogeneic transplantation of UCB cells heterozygous for the CCR5∆32 mutation (UCBΔ32/wt) b) Epigenetic down-regulation of residual CCR5 expression in synergy with improved engraftment. Such treatment has capacity not only to improve engraftment of (UCBΔ32/wt) cells heterozygous for the CCR5∆32 mutation but also prevent functional expression of the CCR5 chemokine receptor used by CCR5 (R5)-tropic HIV-1 to enter CD4 + T cells. Provided that PGE 2 or its more stable analogue dimethyl-PGE 2 (dmPGE 2) has lasting effects in HSCs this could lead to significant increase of the number of treatable patients (frequency of heterozygous CCR5wt/∆32 donors in US and Central and North of Europe is at least 10-fold higher than in the case of homozygous CCR5∆32/∆32 donors). Thus, ultimate goal is to create a functional R5-tropic HIV-1-resistant immune system through the use of optimized dmPGE 2-modified UCB cells heterozygous for ∆32 mutation with improved homing, engraftment, and preferential cord chimerism with further emphasis on post-transplant amelioration of the graft versus host disease (GvHD) enabled via PGE 2-mediated potentiation of regulatory T (Treg) cell-mediated suppression.