Prospects of hematopoietic stem cell transplantation for patients with HIV infection

• Madina M. Gadzhikulieva
• Olga О. Chernysheva
• Elena V. Tsyganova
• Galina А. Dudina

Abstract

At the same time, for about 28% of the causes of deaths in patients with human immunodeficiency virus (HIV) infection are malignant neoplasm, including lymphomas. The hematopoietic stem cell transplantation (HSCT) is one of the main approaches in the treatment of lymphoproliferative diseases (LPDs).

The aim of this study is to conduct a systematic analysis of data and to identify existing approaches and prospects for HSCT in patients with HIV infection.

Material and methods. A systematic review of 66 articles, including 62 from foreign sources, was conducted for the period between 2009 and 2023. The search was conducted using the PubMed, Web of Science, Scopus, and eLibrary databases, as well as Google Scholar.

Results and discussion. HSCT is an indispensable component of the treatment for LPDs in HIV patients, as well as a possible method for eliminating one of the HIV-1 reservoir and controlling viral load. To minimize the risk of re-infection with hematopoietic stem cells (HSCs), it is recommended to use cells carrying the 32-base pair deletion C-C chemokine receptor type 5 (CCR5Δ32/Δ32) mutation. Given the high specificity and potential for wide application, the clustered regularly interspaced short palindromic repeats / CRISPR-associated protein 9 (CRISPR/Cas-9) system seems to be a promising method for editing the HSCs genome.

Conclusion. HSCT in HIV-positive patients is an essential component of LPDs treatment, and can also be considered as a potential means of achieving stable and long-term remission from HIV infection. Further research is needed to fully understand the potential benefits and risks of this approach.

Keywords: HIV-infection; hematopoietic stem cell trans­plan­tation; lym­phopro­liferative diseases; CRISPR/Сas9; ZFN; TALEN

References

1. UNAIDS. 2022 Executive Summary — In Danger: UNAIDS Global AIDS Update 2022. 2022: 1–27.

2. Navarro J.T., Moltó J., Tapia G., Ribera J.M. Hodgkin lymphoma in people living with HIV. Cancers (Basel). 2021; 13 (17): 43–66. DOI: https://doi.org/10.3390/cancers13174366

3. Castelli R., Schiavon R., Preti C., Ferraris L. HIV-related lymphoproliferative diseases in the era of combination antiretroviral therapy. Cardiovasc Hematol Disord Drug Targets. 2020; 20 (3): 175–80. DOI: https://doi.org/10.2174/1871529X20666200415121009

4. Noy A. Optimizing treatment of HIV-associated lymphoma. Blood. 2019; 134 (17): 1385–94. DOI: https://doi.org/10.1182/blood-2018-01-791400

5. Prator C.A., Donatelli J., Henrich T.J. From Berlin to London: HIV-1 reservoir reduction following stem cell transplantation. Curr HIV/AIDS Rep. 2020; 17 (4): 385–93. DOI: https://doi.org/10.1007/s11904-020-00505-2

6. Duarte R.F., Labopin M., Bader P., Basak G.W., et al.; European Society for Blood and Marrow Transplantation (EBMT). Indications for haematopoietic stem cell transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2019. Bone Marrow Transplant. 2019; 54 (10): 1525–52. DOI: https://doi.org/10.1038/s41409-019-0516-2

7. Pang A., Huo Y., Shen B., Zheng Y., et al. Optimizing autologous hematopoietic stem cell transplantation for acute leukemia. Stem Cells Transl Med. 2021; 10: 75–84. DOI: https://doi.org/10.1002/sctm.21-0176

8. Al Hamed R., Bazarbachi A.H., Malard F., et al. Current status of autologous stem cell transplantation for multiple myeloma. Blood Cancer J. 2019; 9 (4): 44. DOI: https://doi.org/10.1038/s41408-019-0205-9

9. Morè S., Corvatta L., Manieri V.M. et al. Autologous stem cell transplantation in multiple myeloma: where are we and where do we want to go? Cells. 2022; 11 (4): 60–6. DOI: https://doi.org/10.3390/cells11040606

10. Balassa K., Danby R., Rocha V. Haematopoietic stem cell transplants: principles and indications. Br J Hosp Med (Lond). 2019; 80 (1): 33–9. DOI: https://doi.org/10.12968/hmed.2019.80.1.33

11. Albert M.H., Slatter M.A., Gennery A.R., et al. Hematopoietic stem cell transplantation for Wiskott-Aldrich syndrome: an EBMT Inborn Errors Working Party analysis. Blood. 2022; 139 (13): 2066–79. DOI: https://doi.org/10.1182/blood.2021014687

12. Alexander T., Greco R., Snowden J.A. Hematopoietic stem cell transplantation for autoimmune disease. Annu Rev Med. 2021; 72: 215–28. DOI: https://doi.org/10.1146/annurev-med-070119-115617

13. Weisdorf D., Cooley S., Wang T., et al. KIR donor selection: feasibility in identifying better donors. Biol Blood Marrow Transplant. 2019; 25 (1): 28–32. DOI: https://doi.org/10.1016/j.bbmt.2018.08.022

14. Osipov Yu.S., Bessmel’tsev S.S., Salogub G.N., et al. Infectious complications after haploidentical hematopoietic stem cell transplantation in patients with high-risk hematopoietic and lymphoid tissue tumors: the experience of one center. Klinicheskaya onkogematologiya [Clinical Oncohematology]. 2019; 12 (4): 406–15. (in Russian)

15. Handgretinger R. Negative depletion of CD3(+) and TcRαβ(+) T cells. Curr Opin Hematol. 2012; 19 (6): 434–9. DOI: https://doi.org/10.1097/MOH.0b013e3283582340

16. Subbotina N.N., Dolgopolov I.S., Popa A.V., et al. Haploidentical hematopoietic stem cell transplantation in children with acute myeloid leukemia: evolution of the method and own data. Klinicheskaya onkogematologiya [Clinical Oncohematology]. 2014; 7 (2): 131–6. (in Russian)

17. Sugita J. HLA-haploidentical stem cell transplantation using posttransplant cyclophosphamide. Int J Hematol. 2019; 110 (1): 30–8. DOI: https://doi.org/10.1007/s12185-019-02660-8

18. Nagler A., Labopin M., Houhou M. et al. Outcome of haploidentical versus matched sibling donors in hematopoietic stem cell transplantation for adult patients with acute lymphoblastic leukemia: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. J Hematol Oncol. 2021; 14 (1): 53. DOI: https://doi.org/10.1186/s13045-021-01065-7

19. Bazinet A., Popradi G. A general practitioner’s guide to hematopoietic stem-cell transplantation. Curr Oncol. 2019; 26 (3): 187–91. DOI: https://doi.org/10.3747/co.26.5033

20. Majhail N.S. Long-term complications after hematopoietic cell transplantation // Hematol. Oncol. Stem Cell Ther. 2017. Vol. 10, N 4. P. 220–227. DOI: https://doi.org/10.1016/j.hemonc.2017.05.009

21. Tsukamoto T. Hematopoietic stem/progenitor cells and the pathogenesis of HIV/AIDS // Front. Cell. Infect. Microbiol. 2020. Vol. 10. P. 60. DOI: https://doi.org/10.3389/fcimb.2020.00060

22. Weichold F.F., Zella D., Barabitskaja O., et al. Neither human immunodeficiency virus-1 (HIV-1) nor HIV-2 infects most-primitive human hematopoietic stem cells as assessed in long-term bone marrow cultures. Blood. 1998; 91 (3): 907–15.

23. Ruiz M.E., Cicala C., Arthos J., et al. Peripheral blood-derived CD34+ progenitor cells: CXC chemokine receptor 4 and CC chemokine receptor 5 expression and infection by HIV. J Immunol. 1998; 161 (8): 4169–76.

24. Carter C.C., Onafuwa-Nuga A., McNamara L.A., et al. HIV-1 infects multipotent progenitor cells causing cell death and establishing latent cellular reservoirs. Nat Med. 2010; 16 (4): 446–51. DOI: https://doi.org/10.1038/nm.2109

25. Sebastian N.T., Zaikos T.D., Terry V., et al. CD4 is expressed on a heterogeneous subset of hematopoietic progenitors, which persistently harbor CXCR4 and CCR5-tropic HIV proviral genomes in vivo. PLoS Pathog. 2017; 13 (7): e1006509. DOI: https://doi.org/10.1371/journal.ppat.1006509

26. Carter C.C., McNamara L.A., Onafuwa-Nuga A., et al. HIV-1 utilizes the CXCR4 chemokine receptor to infect multipotent hematopoietic stem and progenitor cells. Cell Host Microbe. 2011; 9 (3): 223–34. DOI: https://doi.org/10.1016/j.chom.2011.02.005

27. Zaikos T.D., Terry V.H., Sebastian Kettinger N.T., et al. Hematopoietic stem and progenitor cells are a distinct HIV reservoir that contributes to persistent viremia in suppressed patients. Cell Rep. 2018; 25 (13): 3759–73.e9. DOI: https://doi.org/10.1016/j.celrep.2018.11.104

28. Wang C., Liu J., Liu Y. Progress in the treatment of HIV-associated lymphoma when combined with the antiretroviral therapies. Front Oncol. 2022; 11: 798008. DOI: https://doi.org/10.3389/fonc.2021.798008

29. Krishnan A., Palmer J.M., Zaia J.A., et al. HIV status does not affect the outcome of autologous stem cell transplantation (ASCT) for non-Hodgkin lymphoma (NHL). Biol Blood Marrow Transplant. 2010; 16 (9): 1302–8. DOI: https://doi.org/10.1016/j.bbmt.2010.03.019

30. Díez-Martín J.L., Balsalobre P., Re A., et al.; European Group for Blood and Marrow Transplantation Lymphoma Working Party. Comparable survival between HIV+ and HIV- non-Hodgkin and Hodgkin lymphoma patients undergoing autologous peripheral blood stem cell transplantation. Blood. 2009; 113 (23): 6011–4. DOI: https://doi.org/10.1182/blood-2008-12-195388

31. Popova M.O., Rogacheva Yu.A., Chekalov A.M., et al. LY-05. Autologous hematopoietic cell transplantation for HIV-related lymphoma: results of prospective matched case-control study. Kletochnaya terapiya i transplantatsiya [Cell Therapy and Transplantation]. 2022; 11 (3): 1–7. DOI: https://doi.org/10.18620/ctt-1866-8836-2020-9-3-1-152 (in Russian)

32. Afanas’ev B.V., Popova M., Bondarenko S. Allogeneic hematopoietic stem cell transplantation in patients with acute leukemia and HIV infection, the experience of St Petersburg. Kletochnaya terapiya i transplantatsiya [Cell Therapy and Transplantation]. 2015; 4 (1–2): 30–5. DOI: https://doi.org/10.18620/1866-8836-2015-4-1-2-24-30 (in Russian)

33. Hütter G., Zaia J.A. Allogeneic haematopoietic stem cell transplantation in patients with human immunodeficiency virus: the experiences of more than 25 years. Clin Exp Immunol. 2011; 163 (3): 284–95. DOI: https://doi.org/10.1111/j.1365-2249.2010.04312.x

34. Serrano D., Miralles P., Balsalobre P., et al. Graft-versus-tumor effect after allogeneic stem cell transplantation in HIV-positive patients with high-risk hematologic malignancies. AIDS Res Hum Retroviruses. 2013; 29 (10): 1340–5. DOI: https://doi.org/10.1089/AID.2013.0001

35. Lepik K.V., Popova M.O., Shakirova A.I., et al. Gene therapy based on hematopoietic stem cell transplantation using site-specific genome editing. Geny i kletki [Genes and Cells]. 2016; 11 (2): 21–31. (in Russian)

36. Xiao T., Cai Y., Chen B. HIV-1 entry and membrane fusion inhibitors. Viruses. 2021; 13 (5): 735. DOI: https://doi.org/10.3390/v13050735

37. Zhang C., Zhu R., Cao Q., et al. Discoveries and developments of CXCR4-targeted HIV-1 entry inhibitors. Exp Biol Med (Maywood). 2020; 245 (5): 477–85. DOI: https://doi.org/10.1177/1535370220901498

38. Weichseldorfer M., Tagaya Y., Reitz M., et al. Identifying CCR5 coreceptor populations permissive for HIV-1 entry and productive infection: implications for in vivo studies. J Transl Med. 2022; 20 (1): 39. DOI: https://doi.org/10.1186/s12967-022-03243-8

39. Ling L., Hou J., Liu D., et al. Important role of the SDF-1/CXCR4 axis in the homing of systemically transplanted human amnion-derived mesenchymal stem cells (hAD-MSCs) to ovaries in rats with chemotherapy-induced premature ovarian insufficiency (POI). Stem Cell Res Ther. 2022; 13 (1): 79. DOI: https://doi.org/10.1186/s13287-022-02759-6

40. Hütter G., Nowak D., Mossner M., et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med. 2009; 360 (7): 692–8. DOI: https://doi.org/10.1056/NEJMoa0802905

41. Gupta R.K., Abdul-Jawad S., McCoy L.E., et al. HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-cell transplantation. Nature. 2019; 568 (7751): 244–8. DOI: https://doi.org/10.1038/s41586-019-1027-4

42. Smolyaninov A.B., Chechetkin A.V., Zharov E.V., et al. Therapeutic possibilities of transplantation of hematopoietic cord blood stem cells in HIV infection 1. Zhurnal infektologii [Journal of Infectology]. 2013; (4): 3–7. (in Russian)

43. Spellman S.R., Eapen M., Logan B.R., et al.; National Marrow Donor Program; Center for International Blood and Marrow Transplant Research. A perspective on the selection of unrelated donors and cord blood units for transplantation. Blood. 2012; 120 (2): 259–65. DOI: https://doi.org/10.1182/blood-2012-03-379032

44. Rothenberger M., Wagner J.E., Haase A., et al. Transplantation of CCR5∆32 homozygous umbilical cord blood in a child with acute lymphoblastic leukemia and perinatally acquired HIV infection. Open Forum Infect Dis. 2018; 5 (5): ofy090. DOI: https://doi.org/10.1093/ofid/ofy090

45. Hsu J., Van Besien K., Glesby M.J., et al.; International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) P1107 Team. HIV-1 remission and possible cure in a woman after haplo-cord blood transplant. Cell. 2023; 186 (6): 1115–26.e8. DOI: https://doi.org/10.1016/j.cell.2023.02.030

46. Petz L.D., Redei I., Bryson Y., et al. Hematopoietic cell transplantation with cord blood for cure of HIV infections. Biol Blood Marrow Transplant. 2013; 19 (3): 393–7. DOI: https://doi.org/10.1016/j.bbmt.2012.10.017

47. Dobner J., Ramachandran H., Rossi A. Genome editing in translational medicine: an inventory. Front Biosci (Landmark Ed). 2022. 27 (8): 241. DOI: https://doi.org/10.31083/j.fbl2708241

48. Knipping F., Newby G.A., Eide C.R., et al. Disruption of HIV-1 co-receptors CCR5 and CXCR4 in primary human T cells and hematopoietic stem and progenitor cells using base editing. Mol Ther. 2022; 30 (1): 130–44. DOI: https://doi.org/10.1016/j.ymthe.2021.10.026

49. Holt N., Wang J., Kim K., et al. Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo. Nat Biotechnol. 2010; 28 (8): 839–47. DOI: https://doi.org/10.1038/nbt.1663

50. Perez E.E., Wang J., Miller J.C., et al. Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases. Nat Biotechnol. 2008; 26 (7): 808–16. DOI: https://doi.org/10.1038/nbt1410

51. DiGiusto D.L., Cannon P.M., Holmes M.C., et al. Preclinical development and qualification of ZFN-mediated CCR5 disruption in human hematopoietic stem/progenitor cells. Mol Ther Methods Clin Dev. 2016; 3: 16067. DOI: https://doi.org/10.1038/mtm.2016.67

52. Holt N., Wang J., Kim K., et al. Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo. Nat Biotechnol. 2010; 28 (8): 839–47. DOI: https://doi.org/10.1038/nbt.1663

53. Mock U., Machowicz R., Hauber I., et al. mRNA transfection of a novel TAL effector nuclease (TALEN) facilitates efficient knockout of HIV co-receptor CCR5. Nucleic Acids Res. 2015; 43 (11): 5560–71. DOI: https://doi.org/10.1093/nar/gkv469

54. Mock U., Hauber I., Fehse B. Digital PCR to assess gene-editing frequencies (GEF-dPCR) mediated by designer nucleases. Nat Protoc. 2016; 11 (3): 598–615. DOI: https://doi.org/10.1038/nprot.2016.027

55. Romito M., Juillerat A., Kok Y.L., et al. Preclinical evaluation of a novel TALEN targeting CCR5 confirms efficacy and safety in conferring resistance to HIV-1 infection. Biotechnol J. 2021; 16 (1): e2000023. DOI: https://doi.org/10.1002/biot.202000023

56. Matsumoto D., Tamamura H., Nomura W. TALEN-based chemically inducible, dimerization-dependent, sequence-specific nucleases. Biochemistry. 2020; 59 (2): 197–204. DOI: https://doi.org/10.1021/acs.biochem.9b00798

57. Jiang F., Doudna J.A. CRISPR-Cas9 structures and mechanisms. Annu Rev Biophys. 2017; 4: 505–29. DOI: https://doi.org/10.1146/annurev-biophys-062215-010822

58. Maganti H.B., Bailey A.J.M., Kirkham A.M., et al. Persistence of CRISPR/Cas9 gene edited hematopoietic stem cells following transplantation: a systematic review and meta-analysis of preclinical studies. Stem Cells Transl Med. 2021; 10 (7): 996–1007. DOI: https://doi.org/10.1002/sctm.20-0520

59. Mandal P.K., Ferreira L.M., Collins R., et al. Efficient ablation of genes in human hematopoietic stem and effector cells using CRISPR/Cas9. Cell Stem Cell. 2014; 15 (5): 643–52. DOI: https://doi.org/10.1016/j.stem.2014.10.004

60. Liu Z., Chen S., Jin X., et al. Genome editing of the HIV co-receptors CCR5 and CXCR4 by CRISPR-Cas9 protects CD4+ T cells from HIV-1 infection. Cell Biosci. 2017; 7: 47. DOI: https://doi.org/10.1186/s13578-017-0174-2

61. Xiao Q., Chen S., Wang Q., et al. CCR5 editing by Staphylococcus aureus Cas9 in human primary CD4+T cells and hematopoietic stem/progenitor cells promotes HIV-1 resistance and CD4+ T cell enrichment in humanized mice. Retrovirology. 2019; 16 (1): 15. DOI: https://doi.org/10.1186/s12977-019-0477-y

62. Xu L., Yang H., Gao Y., et al. CRISPR/Cas9-mediated CCR5 ablation in human hematopoietic stem/progenitor cells confers HIV-1 resistance in vivo. Mol Ther. 2017; 25 (8): 1782–9. DOI: https://doi.org/10.1016/j.ymthe.2017.04.027

63. Xu L., Wang J., Liu Y., et al. CRISPR-edited stem cells in a patient with HIV and acute lymphocytic leukemia. N Engl J Med. 2019; 381 (13): 1240–7. DOI: https://doi.org/10.1056/NEJMoa1817426

64. Colonna L., Peterson C.W., Schell J.B., et al. Evidence for persistence of the SHIV reservoir early after MHC haploidentical hematopoietic stem cell transplantation. Nat Commun. 2018; 9 (1): 4438. DOI: https://doi.org/10.1038/s41467-018-06736-7

65. Weinfurter J.T., D’Souza S.S., Matschke L.M., et al. Allogeneic MHC-matched T-cell receptor α/β-depleted bone marrow transplants in SHIV-infected, ART-suppressed Mauritian cynomolgus macaques. Sci Rep. 2022; 12 (1): 12345. DOI: https://doi.org/10.1038/s41598-022-16306-z

All articles in our journal are distributed under the Creative Commons Attribution 4.0 International License (CC BY 4.0 license)