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

Journal of Human Virology & Retrovirology Hematopoietic Stem Cell-Based Therapy for HIV Disease: Prostaglandin-Modulated Transplantation Abstract Mini Review Allogeneic stem cell transplantation of hematopoietic stem cells (HSCs) resistant Volume 2 Issue 3 - 2015 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 Josef Bodor1,2* and Petr Kobylka1 E (PGE )- 2 2 1Institute of Hematology and Blood Transfusion, Department mediated mechanisms to facilitate allogeneic transplantation. Since PGE2 has of Cell Therapy and Cord Blood Bank CR, Czech Republic additionalCCR5∆32 mutationcapacity to (UCBΔ32/Δ32) down-regulate CCR5favors expression, utilization thisof prostaglandincould enable dual effect 2Institute of Immunology, Johannes Gutenberg University, a) Germany Allogeneic transplantation of UCB cells heterozygous for the CCR5∆32 b) Epigenetic down-regulation of residual CCR5 expression in synergy with *Corresponding author: Josef Bodor, Institute of mutation (UCBΔ32/wt) Immunology, Johannes Gutenberg University, Langenbeck improved engraftment. street no 1, D-55131 Mainz, Germany, Tel: +420-722-950- 013; Fax: 420-241-062-785; Email: theSuch CCR5 treatment chemokine has capacity receptor not used only by to CCR5 improve (R5)-tropic engraftment HIV-1 ofto (UCBΔ32/wt)enter CD4+ T cells.cells Received: February 19, 2015 | Published: March 19, 2015 heterozygous for the CCR5∆32 mutation but also prevent functional expression of Provided that PGE2 or its more stable analogue dimethyl-PGE2(dmPGE2) has lasting effects in HSCs this could lead to significant increase of the number of treatable donors).patients (frequencyThus, ultimate of heterozygous goal is to create CCR5wt/∆32 a functional donors R5-tropic in US HIV-1-resistant and Central and immune North of Europe is at least 10-fold higher than in the case of homozygous CCR5∆32/∆32 system through the use of optimized dmPGE2 with further emphasis on post-transplant amelioration-modified of theUCB graft cells versus heterozygous host disease for ∆32 mutation with improved homing, engraftment, and preferential cord chimerism (GvHD) enabled via PGE2-mediated potentiation of regulatory T (Treg) cell-mediated suppression. Keywords: CCR5; HIV-1; HSC; UCB; PGE2; dmPGE2; GvHD; nTregs; iTregs; Tcons; cAMP; ICER Abbreviations: CCR5: Chemokine C-C Motif Receptor 5; HIV- locusis an urgentis present need in to Europe, repeat withtransplantation higher frequencies using CCR5∆32/∆32 in the north Stem Cell; UCB: Umbilical Cord Blood; PGE2: Prostaglandin E2; 1: Human Immunodeficiency Virus type-1; HSC: Hematopoietic HSCs resistant to HIV. Importantly the ∆32 mutation at the CCR5 dmPGE2: Dimethyl Prostaglandin E2; GvHD: Graft-Versus-Host +CD25+ T are resistant to HIV-1 infection of R5 strain because the mutation Cells; iTregs: Inducible Tregs; Tcons: Conventional CD4+ T Cells; prevents[3] and homozygous functional expressioncarriers of the of the∆32 CCR5 mutation chemokine (CCR5∆32/∆32) receptor cAMP:Disease; Cyclic nTregs: AMP; Naturally ICER: Inducible Occurring cAMP Regulatory Early Repressor CD4 used by HIV-1 to enter CD4+ T cells while heterozygous carriers have partial resistance to HIV-1 infection of R5 strain. The concept Introduction of allogeneic stem cell transplantation of the cells resistant to HIV (CCR5 null cells) using a regimen to improve and modulate Evidence for the cure of HIV infection by CCR5∆32/∆32 engraftment of umbilical cord blood cells (UCB) homozygous for stem cell transplantation E2 (PGE2)- The unprecedented power of the hematopoetic stem cell mediated mechanisms to facilitate both allogeneic transplantation CCR5∆32 mutation favors utilization of prostaglandin HIV has been reported in 2009 to cure HIV infection in the case cells of heterozygous donors with partial protection against HIV of(HSC) leukemia transplantation patient infected of the with CCR5∆32/∆32 HIV (‘Berlin patient’cells resistant - Timothy to infection).and downregulation of CCR5 expression (critical in (UCBΔ32/wt) Inhibitory pathway of PGE in Tcons patient ‘remains HIV free without any antiretroviral treatment 2 (ART).Ray Brown) Another [1]. twoMore cases than control five years HIV after infection transplantation only temporarily ‘Berlin An important precedent of receptor mediated cAMP after HSC transplantation of bone marrow cells treated with ART formation in inducible Tregs (iTregs) is prostaglandin E2 (PGE2) [2]. These two cases reported from Brigham and Women Hospital synthesis [4]. It has been demonstrated that iTregs express in Boston clearly demonstrated that use of bone marrow donors 2 upon differentiation, signaling through any of its four receptors – EP1, EP2, EP3, and treatment and may purge latent reservoirs of HIV. Currently, EP4-oftencyclooxygenase-2 with opposing (COX-2) effects.and produce EP2 and PGE EP4 appear to be the with CCR5∆32/∆32 cells resistant to HIV are superior to ART most abundant in naïve cells isolated from peripheral blood and are up-regulated in response to activation. Recent studies have CCR5∆32/∆32 HSCs promise sterilizing immunity against HIV. Since ‘Berlin patient’ is the first man cured of HIV infection, there Submit Manuscript raveonline.com Hum Virol Retrovirol 2015, 2(3): 00040 | http://medc Hematopoietic stem cell-based therapy for HIV disease: Prostaglandin-modulated Copyright: 2/4 transplantation ©2015 Bodor et al. PAG scaffold, process phosphorylation of the C-terminal Src described in conventional CD4+ T cells (Tcons) where signaling kinase (Csk). Phosphorylated Csk in turn inhibits Lck-mediated throughprovided EP2significant or EP4, insights, with its in concomitantparticular, a pathwayincrease hasin cAMPbeen phosphorylation of the TCR complex, thus inhibiting TCR signaling levels, leads to PKA activation and, through an EBP50-Ezrin- and T cell proliferation and function (Figure 1). Figure 1: Model of inhibitory pathway of prostaglandin E2 (PGE2) and down regulation of CCR5 in Tcons. PGE2 mediates Treg inhibition of Tcon function through a PKA- mediated pathway: 2–4 h of delay, necessary for ICER synthesis) in the Foxp3[6,7]. Inneg Tconsresponse and to later cAMP/PKA, ICER protein ICER is is enforced induced to(after the 1) In response to continuous antigen exposure, for instance in cancer and HIV, adaptive regulatory T cells express CCR5 expression in cAMP dependent fashion (Figure 2). , which stimulates 2 nucleus in response to cAMP/PKA where it may attenuate cyclooxygenase-2 (COX-2) and PGE PGE2 can signal through EP2 and EP4 receptors on Tcons toFOXP3 inhibit expression the function in these of these cells cells[4]. Thethrough Treg-derived pathway shown in Figure 1. 2) Binding of PGE2 to its receptors on Tcons stimulates adenylyl cyclase activity, which increases intracellular cAMP levels and thus activates PKA. Aided by an Ezrin- EBP50-PAG scaffold, PKA phosphorylates Csk, which in turn phosphorylates Lck to inhibit its activity. Lck normally acts to promote TCR signaling; thus Lck inhibition through this PGE2-initiated pathway inhibits TCR signaling in Tcons. 3) Cyclic AMP (cAMP) underpins suppression by nTreg cells. Upon TCR activation (not shown), prostaglandin E2 (PGE2) leads to activation of adenylyl cyclase, intracellular cAMP formation [5], and subsequent protein kinase A (PKA) activation(not shown) followed by the immediate, early induction of inducible cAMP early repressor (ICER) in TCR-activated Foxp3neg Tcons [6]. Analogous effect could be achieved by direct activation of adenylyl cyclase (AC) Figure 2: PGE2-mediated transcriptional attenuation of CCR5 by forskolin or inhibition of phosphodiesterases (PDEs) chemokine receptor expression correlates with ICER induction. responsible for degradation of cAMP e.g. by Rolipram Citation: Bodor J, Kobylka P (2015) Hematopoietic stem cell-based therapy for HIV disease: Prostaglandin-modulated transplantation. J Hum Virol Retrovirol 2(3): 00040. DOI: 10.15406/jhvrv.2015.02.00040 Hematopoietic stem cell-based therapy for HIV disease: Prostaglandin-modulated Copyright: 3/4 transplantation ©2015 Bodor et al. Human monocytes were treated with PGE (Figure 2) and scored for 2 2 production from iTregs can be human chemokine receptor expression (left panel) in parallel with ICER nTregs express COX-2. The PGE data indicate that PGE2 plays an important role in differentiation evaluation of human chemokine receptor expression, a Riboquant hCR8 offully HSCs suppressed thus releasing by the stringencyCOX inhibitor required indomethacin for HLA-matching [4]. These probeexpression set was (right used. panel), Levels using of chemokine RNase protection receptor assaywere evaluated(Ambion). after For 0 donors with potential recipients as well as with potential role PGE2 C in regular media). 2 treatment. treatment Templates (500 ng/ml for the final analysis for 1h of andhL32 2h and at 37human glyceraldehyde- acquired ability to produce copious amounts of PGE2 responsible 3-phosphateLevels of CCR5 dehydrogenase are inversely related housekeeping to the levels genes of were ICER includedmRNA after to allow PGE forin dominant delivery ofsuppressive suppressive effects function of iTregs through expressing elevated COX-2 levels with of cAMP [12,13]. assessment of total RNA levels. Unresolved questions of PGE2-mediated down Conclusion regulation of CCR5 Prostaglandin E2 (PGE2)-mediated mechanisms, which PGE2-mediated transcriptional attenuation of CCR5 chemokine have potential to down-regulate CCR5 expression in umbilical

Load more