Progress Toward Curing HIV Infection with Hematopoietic Cell Transplantation
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Stem Cells and Cloning: Advances and Applications Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Progress toward curing HIV infection with hematopoietic cell transplantation Lawrence D Petz1 Abstract: HIV-1 infection afflicts more than 35 million people worldwide, according to John C Burnett2 2014 estimates from the World Health Organization. For those individuals who have access 3 Haitang Li to antiretroviral therapy, these drugs can effectively suppress, but not cure, HIV-1 infection. Shirley Li3 Indeed, the only documented case for an HIV/AIDS cure was a patient with HIV-1 and acute Richard Tonai1 Milena Bakalinskaya4 myeloid leukemia who received allogeneic hematopoietic cell transplantation (HCT) from Elizabeth J Shpall5 a graft that carried the HIV-resistant CCR5-∆32/∆32 mutation. Other attempts to establish a Sue Armitage6 cure for HIV/AIDS using HCT in patients with HIV-1 and malignancy have yielded mixed Joanne Kurtzberg7 results, as encouraging evidence for virus eradication in a few cases has been offset by poor 8 Donna M Regan clinical outcomes due to the underlying cancer or other complications. Such clinical strate- Pamela Clark9 gies have relied on HIV-resistant hematopoietic stem and progenitor cells that harbor the Sergio Querol10 Jonathan A Gutman11 natural CCR5-∆32/∆32 mutation or that have been genetically modified for HIV-resistance. Stephen R Spellman12 Nevertheless, HCT with HIV-resistant cord blood remains a promising option, particularly Loren Gragert13 with inventories of CCR5-∆32/∆32 units or with genetically modified, human leukocyte 2 John J Rossi antigen-matched cord blood. 1StemCyte International Cord Blood Center, Keywords: curing HIV infection, hematopoietic cell transplantation, genetic modification of Baldwin Park, CA, USA; 2Department of Molecular and Cellular Biology, Irell and stem cells, CCR5 mutation, CCR5-∆32/∆32 cord blood inventory Manella Graduate School of Biological Sciences, 3Department of Molecular and Cellular Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA; 4CCR5-∆32/∆32 Introduction and background Research Department, StemCyte International Antiretroviral therapy (ART) inhibits various stages in the viral life cycle, reduces Cord Blood Center, Baldwin Park, CA, USA; 5Department of Stem Cell Transplantation, the rates of transmission, and improves life expectancy. Unfortunately, ART is non- University of Texas MD Anderson Cancer Center, Houston, TX, USA; 6MD Anderson curative, and nearly all HIV-infected individuals must adhere to daily drug regimens Cord Blood Bank, Department of Stem Cell Transplantation, University of Texas MD for the entirety of their lives. This requirement indefinitely prolongs issues such as Anderson Cancer Center, Houston, TX, USA; drug resistance, adverse effects, and cost.1 While ART extends and improves the 7Carolinas Cord Blood Bank, Duke University Medical Center, Durham, NC, USA; 8St Louis quality of life, it does not fully restore health. Individuals on ART can experience Cord Blood Bank, SSM Cardinal Glennon Children’s Medical Center, St Louis, MO, USA; chronic inflammation, immunosenescence, bone density loss, premature aging, 9 Enhance Quality Consulting Inc., Oviedo, FL, 2 USA; 10Cell Therapy Service and Cord Blood and increased non-AIDS morbidity and mortality. ART treatment interruptions in Bank, Banc de Sang i Teixits, Barcelona, Spain; aviremic HIV-infected individuals lead to rapid viral recrudescence that reaches 11BMT/Hematologic Malignancies, University of Colorado, Aurora, CO, USA; 12Immunobiology pretreatment levels.3 Thus, suppression of viral replication with ART does not eradi- and Observational Research, CIBMTR, + Minneapolis, MN, USA; 13National Marrow cate the virus, as long-lived resting memory CD4 T-cells can harbor latent virus, Donor Program/Be The Match, Minneapolis, MN, USA and while various reservoirs may produce low-levels of virus, such as microglia and astrocytes in the central nervous system, tissue-derived dendritic cells, macrophages, Correspondence: Lawrence D Petz and natural killer cells.4 Further complicating matters, latently infected T-cells may StemCyte International Cord Blood Center, 13800 Live Oak Avenue, undergo clonal expansion by homeostatic proliferation,5 while infected T-cells and Baldwin Park, CA 91706, USA macrophages can persist without undergoing apoptosis or cytotoxic T-lymphocytes Tel +1 626 646 2502 Email [email protected] (CTL)-induced killing.6,7 submit your manuscript | www.dovepress.com Stem Cells and Cloning: Advances and Applications 2015:8 109–116 109 Dovepress © 2015 Petz et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further http://dx.doi.org/10.2147/SCCAA.S56050 permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Petz et al Dovepress Due to persistence of infection during ART, alternative International Cord Blood Center and is available for use for therapeutic strategies are being explored to establish a cure appropriate patients. for HIV-1. Current and emerging approaches to eradicate HIV include transplanting virus-resistant hematopoietic HCT using CCR5-∆32/∆32 cord blood stem and progenitor cells (HSPCs) in an effort to generate units an HIV-resistant immune system. To achieve HIV resis- Units from StemCyte’s inventory of CCR5-∆32/∆32 cord tance, much focus has been placed on natural mutation of or blood units have been used for allogeneic HCT in patients engineered inhibition of the endogenous chemokine recep- with HIV infection. One of the transplants was performed tor CCR5.8 Owing to the role of CCR5 as a co-receptor for by Dr Rafael F Duarte in Barcelona, Spain using dual hap- HIV entry in CCR5+ CD4+ T-cells, homozygous carriers loidentical/cord blood transplantation in a patient with dif- of a 32-bp deletion in the CCR5 gene (CCR5-∆32/∆32) fuse large B-cell lymphoma and HIV infection.16 Neutrophil are naturally resistant to HIV.9,10 As an alternative to using engraftment, derived from the haploidentical donor, occurred allogeneic CCR5-∆32/∆32 HSPCs from human leuko- on day +11. The cord blood was found to have a poor clono- cyte antigen (HLA)-matched adult or cord blood donors genic capacity, and donor switch to cord blood origin failed, who have this homozygous mutation, genome editing with a persistently low cord blood chimera of ,5% for up to or gene therapy strategies aim to use therapeutic genes 7 weeks. A second CCR5-∆32/∆32 cord blood was infused that disrupt CCR5 genetically or post-transcriptionally, on day +52, leading to a very rapid increase in chimerism respectively. which was from the first cord blood unit and which reached 100% by day +73. At this point, the patient’s hematopoiesis, Cure of HIV infection with hematopoietic including CD4+ T-lymphocytes, became CCR5-∆32/∆32. cell transplantation (HCT) Ultrasensitive plasma viral load analysis decreased soon after The only known cure of HIV infection has resulted from HCT, reaching minimal levels at the time of full cord blood HCT. This has been accomplished by Hütter et al11 with HCT chimerism. No HIV-1 DNA was detected using droplet digital using peripheral blood stem cells from an HLA-matched adult polymerase chain reaction quantification or semiquantitative donor who had the CCR5-∆32/∆32 mutation. The patient has tests of amplification. Importantly, although recipient CD4+ remained without any evidence of HIV infection for more T-cells responded to proliferation and activation stimuli, they than 8 years after discontinuation of antiretroviral drug were resistant to infection by the patient’s isolate as well as by therapy, and the consensus is that he has been cured. laboratory-adapted HIV-1 strains. Unfortunately, the patient However, identifying a HLA-matched adult CCR5-∆32/ developed an aggressive diffuse large B-cell lymphoma pro- ∆32 donor for a given patient is not readily feasible in part gression, and following very rapid clinical deterioration, died because the prevalence of the homozygous variant allele is from disease progression 3 months after HCT.16 only about 0.8%–1% of individuals of northern European In addition, as testing of cord blood units for the CCR5 descent12,13 and much less in other ethnic groups.14 Further, mutation was being carried out, a HCT using a unit that was when an adult donor is used for a HCT, a very close HLA subsequently determined to be CCR5-∆32/∆32 was pro- match between donor and patient is required. Accordingly, vided to an adult patient with acute myelogenous leukemia finding an adult donor who has a very close HLA match to who was not infected with HIV. This unit was transplanted a patient in need of a transplant and who is also homozy- as part of a double cord blood transplant. This unexpected gous for the CCR5-∆32 allele is extremely difficult and event provided the opportunity to collect post-transplant will only rarely be possible. In contrast, cord blood CCR5- data, which indicated engraftment of the CCR5-∆32/∆32 ∆32/∆32 units provide a major advantage in that much less unit as the “winning unit”. At a time when