Hematopoietic cell transplantation with cord blood for cure of HIV infections

Abstract

Hematopoietic cell transplantation (HCT) using CCR5-Δ32/Δ32 stem cells from an adult donor has resulted in the only known cure of human immunodeficiency virus (HIV) infection. However, it is not feasible to repeat this procedure except rarely because of the low incidence of the CCR5-Δ32 allele, the availability of only a small number of potential donors for most patients, and the need for a very close human leukocyte antigen (HLA) match between adult donors and recipients. In contrast, cord blood (CB) transplantations require significantly less stringent HLA matching. Therefore, our hypothesis is that cure of HIV infections by HCT can be accomplished much more readily using umbilical CB stem cells obtained from a modestly sized inventory of cryopreserved CCR5-Δ32/Δ32 CB units. To test this hypothesis, we developed a screening program for CB units and are developing an inventory of CCR5-Δ32/Δ32 cryopreserved units available for HCT. Three hundred such units are projected to provide for white pediatric patients a 73.6% probability of finding an adequately HLA matched unit with a cell dose of ≥2.5 × 10(7) total nucleated cells (TNCs)/kg and a 27.9% probability for white adults. With a cell dose of ≥1 × 10(7) TNCs/kg, the corresponding projected probabilities are 85.6% and 82.1%. The projected probabilities are lower for ethnic minorities. Impetus for using CB HCT was provided by a transplantation of an adult with acute myelogenous leukemia who was not HIV infected. The HCT was performed with a CCR5-Δ32/Δ32 CB unit, and posttransplantation in vitro studies indicated that the patient's peripheral blood mononuclear cells were resistant to HIV infection.

Figure 1

Figure 1A In vitro study of infectivity by HIV-1 of peripheral blood mononuclear cells (PBMCs) in the posttransplant period from an HIV uninfected patient transplanted with a CCR5-Δ32/Δ32 cord blood. The recipient’s PBMCs showed no significant infection with either lab strains of HIV-1, BAL (CCR tropic) and NL4-3 (CXCR4) compared to a normal adult control. Figure 1B A comparison of HIV replication in vitro with the laboratory CCR5 strain HIV-1 BAL for cord blood PBMCs from normal CCR5 wild type, heterozygous and homozygous units. There was no detectable replication in vitro in the CCR5-Δ32/Δ32 cord cells compared to significant replication in the heterozygote and wild type cord cells.

Figure 1

Figure 1A In vitro study of infectivity by HIV-1 of peripheral blood mononuclear cells (PBMCs) in the posttransplant period from an HIV uninfected patient transplanted with a CCR5-Δ32/Δ32 cord blood. The recipient’s PBMCs showed no significant infection with either lab strains of HIV-1, BAL (CCR tropic) and NL4-3 (CXCR4) compared to a normal adult control. Figure 1B A comparison of HIV replication in vitro with the laboratory CCR5 strain HIV-1 BAL for cord blood PBMCs from normal CCR5 wild type, heterozygous and homozygous units. There was no detectable replication in vitro in the CCR5-Δ32/Δ32 cord cells compared to significant replication in the heterozygote and wild type cord cells.

Figure 1

Figure 1A In vitro study of infectivity by HIV-1 of peripheral blood mononuclear cells (PBMCs) in the posttransplant period from an HIV uninfected patient transplanted with a CCR5-Δ32/Δ32 cord blood. The recipient’s PBMCs showed no significant infection with either lab strains of HIV-1, BAL (CCR tropic) and NL4-3 (CXCR4) compared to a normal adult control. Figure 1B A comparison of HIV replication in vitro with the laboratory CCR5 strain HIV-1 BAL for cord blood PBMCs from normal CCR5 wild type, heterozygous and homozygous units. There was no detectable replication in vitro in the CCR5-Δ32/Δ32 cord cells compared to significant replication in the heterozygote and wild type cord cells.