Biol Blood Marrow Transplant 2013 March;19(3):393-397

Hematopoietic Cell Transplantation with Cord Blood for Cure of HIV Infections


Lawrence D. Petz 1, Istvan Redei 2, Yvonne Bryson 3, Donna Regan 4, Joanne Kurtzberg 5, Elizabeth Shpall 6, Jonathan Gutman 7, Sergio Querol 8, Pamela Clark 9, Richard Tonai 1, Sarah Santos 1, Aide Bravo 1, Stephen Spellman 10, Loren Gragert 10, John Rossi 11, Shirley Li 11, Haitang Li 11, David Senitzer 11, John Zaia 11, Joseph Rosenthal 11, Stephen Forman 11, Robert Chow12


1 StemCyte International Cord Blood Center, Covina, CA
2 Midwestern Regional Medical Center, Zion, IL
3 David Geffen School of Medicine at UCLA, Los Angeles, CA
4 St. Louis Cord Blood Bank at Cardinal Glennon Children’s Medical Center, St. Louis, MO
5 Carolinas Cord Blood Bank, Duke University Medical Center, Durham, NC
6 University of Texas M.D. Anderson Cancer Center, Houston, TX
7 University of Colorado Hospital, Denver, CO
8 Barcelona Cord Blood Bank, Barcelona, Spain
9 Sydney Cord Blood Bank, Sydney, Australia
10 National Marrow Donor Program, Minneapolis, MN
11 City of Hope Medical Center, Duarte, CA
12 HMD Consulting, Irvine, CA



Dr. Lawrence Petz



Hematopoietic cell transplantation (HCT) using CCR5-D32/D32 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-D32 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-D32/D32 CB units. To test this hypothesis, we developed a screening program for CB units and are developing an inventory of CCR5-D32/D32 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 x 107 total nucleated cells (TNC)/kg and a 27.9% probability for white adults. With a cell dose of ≥1 x 107 x TNC/kg, the corresponding projected probabilities are 85.6% and 82.1%. The projected probabilities are lower for ethnic minorities.



More than forty years after the onset of the HIV pandemic the disease has not been cured using highly active antiretroviral treatment, by gene therapy, or by HCT using cells from the general pool of stem cell donors. The most important reason for natural protection against HIV transmission is a mutation in the CCR5 gene leading to a 32-base-pair deletion (CCR5-D32/D32) (1). In February 2007, Hütter et al. (2) performed a HCT in a patient with acute myelogenous leukemia who was infected with HIV using stem cells obtained from the peripheral blood of a donor who was homozygous for the CCR5-D32/D32 deletion. More than 6 years after the transplant the patient does not require antiretrovial therapy and there has been no detectable HIV in the blood stream as determined by analysis of viral RNA and cellular proviral DNA. In addition, the CD4+ T cells have returned to a normal range. Therefore, the investigators have concluded that transplantation of homozygous CCR5-D32 stem cells has led to a functional cure or a “sterilizing cure” of HIV infection.

One would expect that such a successful procedure would be performed repeatedly in other HIV-infected patients. Obstacles to frequent use of HCT for cure of HIV are that persons who are homozygous for the CCR5-D32 allele are quite unusual (<1% of Caucasians, and much lower in other ethnic groups), and most patients in need of an HCT have only a small number of potential donors from among registries of adult volunteer donors. Moreover, when the donor stem cells are obtained from adults, as in bone marrow or peripheral blood stem cell transplants, a very close HLA match is required between donors and recipients for 8 of 8 or 7 of 8 high-resolution alleles at 4 loci (A, B, C, DRB1). Thus, finding a donor who has a very close HLA match to a patient in need of a transplant and who is also homozygous for the CCR5-D32 allele is extremely difficult and will only rarely be possible. Indeed, no further HCTs of patients with HIV infection using homozygous CCR5-D32 stem cells from adult donors have been performed.

In marked contrast is the fact that using stem cells from umbilical cord blood for HCT provides a major advantage in that much less stringent HLA matching between donor and recipient are required. Indeed, acceptable HLA-matched units include those that are matched at 4 of 6, 5 of 6, or 6 of 6 alleles at 3 loci using low resolution testing at the A and B loci and high resolution testing at the DRB1 locus, disallowing 2 mismatches at the same locus for 4 of 6 matching. Therefore, our hypothesis is that an inventory of cryopreserved umbilical cord blood units that are homozygous for the CCR5-D32 allele will provide a significantly improved probability of finding an appropriately HLA-matched homozygous CCR5-D32 donor for HCT of a patient with HIV infection.

To test this hypothesis, we are developing an inventory of cryopreserved homozygous CCR5-D32 cord blood units to be used for HCT of appropriate patients. We have tested samples from approximately 25,000 cryopreserved cord blood units obtained primarily from Caucasians and have identified 180 homozygous CCR5-D32 units for an incidence of approximately 0.8%. Testing an additional 15,000 samples from Caucasians is expected to increase the special inventory to about 300 units.

Testing of large numbers of samples requires the collaboration of multiple cord blood banks since no single bank has enough units. Collaborating cord blood banks are St. Louis; Duke University; University of Colorado; MD Anderson Cancer Center; Sydney, Australia; and Barcelona, Spain. CCR5 genotype analysis is performed on DNA extracted from cord blood using a PCR based assay for homozygosity of the CCR5-D32 bp deletion.

Biomathematicians at the National Marrow Donor Program (NMDP) have developed estimates regarding the probability of being able to provide an adequately HLA matched cord blood unit with an adequate cell dose for a patient from among an inventory of 300 homozygous CCR5-D32 units.  Such projections were calculated considering a commonly used value for a minimum cell dose of 2.5 x 107 total nucleated cells (TNC)/kg. Since Liu et al. (3) have reported that a cord blood cell dose as low as 1 x 107TNC/kg body weight is adequate for cord blood transplants done in association with a haploidentical transplant, projections were also made regarding the probability of finding an adequately matched unit in a 300 unit inventory using this as the minimum necessary dose. Such projections indicate a probability of finding an adequately HLA matched unit with a cell dose requirement of ≥1 x 107TNC/kg of 85.6% for Caucasian pediatric patients and 82.1% for Caucasian adult patients. For members of minority ethnic groups, the projections are significantly lower. (Table 1)

Table 1

Projected HLA Match Rates with a 300-Unit Inventory of CCR5-D32/D32 Cord Blood Units

 Lawrence D. Petz-1


The most obvious patient population for the transplantation of homozygous CCR5-D32 cord blood units is that group of patients who are in need of a HCT for a hematologic malignancy or other indication, and are also infected with HIV. The major risks associated with this approach are those related to transplant related morbidity and mortality. Since HCT is indicated for the underlying disorder, the risks associated with HCT would need to be borne by the patient in any case. Nevertheless, when selecting a homozygous CCR5-D32 unit to be used for transplantation of an HIV-infected patient who also has an independent indication for HCT, there may well be alternative donor units available that are not CCR5-negative and that have a higher cell dose and/or better HLA match. In such cases the transplant physician needs to discuss with the patient the risks and benefits of using a lesser well-matched unit that has the potential to cure the HIV infection as well as the underlying malignancy.

In addition, selected patients with AIDS should also be considered for a clinical trial using homozygous CCR5-D32 cord blood donors. Antiretroviral drugs have dramatically improved the prognosis for HIV-infected patients. However, anti-retroviral therapy for HIV infection needs lifelong access and strict adherence to regimens that are both expensive and associated with toxic effects. Thus, patients with AIDS who have responded poorly to antiviral regimens, have a poor prognosis, and who are informed of the significant risks and the potential benefits of HCT should be allowed to participate in a clinical trial of HCT if an appropriately HLA matched homozygous CCR5-D32 unit of adequate cell dose is available.

In summary, HCT using peripheral blood stem cells from an adult donor homozygous for CCR5-D32 has produced a cure of an HIV-infected person. Other therapeutic approaches including the use of antiretroviral drugs or gene therapy have not been successful. However, homozygous CCR5-D32 donors are quite unusual, and this coupled with the fact that the use of stem cells from peripheral blood and bone marrow requires a very close HLA match between the donor and recipient makes it impossible to frequently perform HCT using homozygous CCR5-D32 stem cells from adult donors for patients in need of treatment for HIV.

Therefore, since HCT using cord blood does not require as stringent an HLA match, CCR5-D32/D32 cord blood cells are eminently practical for transplantation to patients who have an indication for a HCT and who are infected with HIV. Further, it must be recognized that HCT using cord bloods from donors homozygous for CCR5-D32 is, at the present time, the only feasible means of treatment of reasonably large numbers of HIV-infected patients.



1. Samson M, Libert F, Doranz BJ et al. Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 1996; 382(6593):722-7

2. Hütter G, Nowak E, Mossner M. Long-term control of  HIV by CCR5 Δ32/Δ32 stem cell transplantation. New Eng J Med 2009; 360(7):692-698.

3. Liu H, Rich ES, Godley L et al. Reduced-intensity conditioning with combined haploidentical and cord blood transplantation results in rapid engraftment, low GVHD, and durable remissions. Blood 2011;118(24):6438-6445.


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