Transplantation of CCR5∆32 homozygous umbilical cord blood in a child with acute lymphoblastic leukemia and perinatally acquired HIV infection

Meghan Rothenberger, John E. Wagner, Ashley Haase, Douglas Richman, Bartosz Grzywacz, Matthew Strain, Steven Lada, Jacob Estes, Courtney V. Fletcher, Anthony T. Podany, Jodi Anderson, Thomas Schmidt, Steve Wietgrefe, Timothy Schacker, Michael R. Verneris

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Background. Allogeneic hematopoietic cell transplantation (allo-HCT) in a CCR5∆32 homozygous donor resulted in HIV cure. Understanding how allo-HCT impacts the HIV reservoir will inform cure strategies. Methods. A 12-year-old with perinatally acquired, CCR5-tropic HIV and acute lymphoblastic leukemia underwent myeloablative conditioning and umbilical cord blood (UCB) transplantation from a CCR5∆32 homozygous donor. Peripheral blood mononuclear cells (PBMCs) and the rectum were sampled pre- and post-transplant. The brain, lung, lymph node (LN), stomach, duodenum, ileum, and colon were sampled 73 days after transplantation (day +73), when the patient died from graft-vs-host disease. Droplet digital polymerase chain reaction (ddPCR) and in situ hybridization (ISH) were used detect the HIV reservoir in tissues. CCR5 and CD3 expression in the LN was assessed using immunohistochemistry (IHC). Results. HIV DNA (vDNA) was detected in PBMCs by ddPCR pretransplant but not post-transplant. vDNA was detected by ISH in the rectum at days -8 and +22, and in the LN, colon, lung, and brain day +73. vDNA was also detected in the lung by ddPCR. IHC revealed CCR5+CD3+ cells in the LN postmortem. Conclusions. HIV was detected in multiple tissues 73 days after CCR5∆32 homozygous UCB allo-HCT despite myeloablative conditioning and complete donor marrow engraftment. These results highlight the importance of analyzing tissue during HIV cure interventions and inform the choice of assay used to detect HIV in tissue reservoirs.

Original languageEnglish (US)
JournalOpen Forum Infectious Diseases
Volume5
Issue number5
DOIs
StatePublished - Jan 1 2018

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Fetal Blood
Precursor Cell Lymphoblastic Leukemia-Lymphoma
HIV Infections
Transplantation
HIV
Cell Transplantation
Lymph Nodes
Tissue Donors
Transplants
Rectum
Polymerase Chain Reaction
Lung
In Situ Hybridization
Blood Cells
Colon
Immunohistochemistry
Brain
Graft vs Host Disease
Ileum
Duodenum

Keywords

  • Allogeneic bone marrow transplantation
  • CCR5∆32
  • HIV cure
  • HIV reservoirs

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology

Cite this

Transplantation of CCR5∆32 homozygous umbilical cord blood in a child with acute lymphoblastic leukemia and perinatally acquired HIV infection. / Rothenberger, Meghan; Wagner, John E.; Haase, Ashley; Richman, Douglas; Grzywacz, Bartosz; Strain, Matthew; Lada, Steven; Estes, Jacob; Fletcher, Courtney V.; Podany, Anthony T.; Anderson, Jodi; Schmidt, Thomas; Wietgrefe, Steve; Schacker, Timothy; Verneris, Michael R.

In: Open Forum Infectious Diseases, Vol. 5, No. 5, 01.01.2018.

Research output: Contribution to journalArticle

Rothenberger, M, Wagner, JE, Haase, A, Richman, D, Grzywacz, B, Strain, M, Lada, S, Estes, J, Fletcher, CV, Podany, AT, Anderson, J, Schmidt, T, Wietgrefe, S, Schacker, T & Verneris, MR 2018, 'Transplantation of CCR5∆32 homozygous umbilical cord blood in a child with acute lymphoblastic leukemia and perinatally acquired HIV infection', Open Forum Infectious Diseases, vol. 5, no. 5. https://doi.org/10.1093/ofid/ofy090
Rothenberger, Meghan ; Wagner, John E. ; Haase, Ashley ; Richman, Douglas ; Grzywacz, Bartosz ; Strain, Matthew ; Lada, Steven ; Estes, Jacob ; Fletcher, Courtney V. ; Podany, Anthony T. ; Anderson, Jodi ; Schmidt, Thomas ; Wietgrefe, Steve ; Schacker, Timothy ; Verneris, Michael R. / Transplantation of CCR5∆32 homozygous umbilical cord blood in a child with acute lymphoblastic leukemia and perinatally acquired HIV infection. In: Open Forum Infectious Diseases. 2018 ; Vol. 5, No. 5.
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abstract = "Background. Allogeneic hematopoietic cell transplantation (allo-HCT) in a CCR5∆32 homozygous donor resulted in HIV cure. Understanding how allo-HCT impacts the HIV reservoir will inform cure strategies. Methods. A 12-year-old with perinatally acquired, CCR5-tropic HIV and acute lymphoblastic leukemia underwent myeloablative conditioning and umbilical cord blood (UCB) transplantation from a CCR5∆32 homozygous donor. Peripheral blood mononuclear cells (PBMCs) and the rectum were sampled pre- and post-transplant. The brain, lung, lymph node (LN), stomach, duodenum, ileum, and colon were sampled 73 days after transplantation (day +73), when the patient died from graft-vs-host disease. Droplet digital polymerase chain reaction (ddPCR) and in situ hybridization (ISH) were used detect the HIV reservoir in tissues. CCR5 and CD3 expression in the LN was assessed using immunohistochemistry (IHC). Results. HIV DNA (vDNA) was detected in PBMCs by ddPCR pretransplant but not post-transplant. vDNA was detected by ISH in the rectum at days -8 and +22, and in the LN, colon, lung, and brain day +73. vDNA was also detected in the lung by ddPCR. IHC revealed CCR5+CD3+ cells in the LN postmortem. Conclusions. HIV was detected in multiple tissues 73 days after CCR5∆32 homozygous UCB allo-HCT despite myeloablative conditioning and complete donor marrow engraftment. These results highlight the importance of analyzing tissue during HIV cure interventions and inform the choice of assay used to detect HIV in tissue reservoirs.",
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T1 - Transplantation of CCR5∆32 homozygous umbilical cord blood in a child with acute lymphoblastic leukemia and perinatally acquired HIV infection

AU - Rothenberger, Meghan

AU - Wagner, John E.

AU - Haase, Ashley

AU - Richman, Douglas

AU - Grzywacz, Bartosz

AU - Strain, Matthew

AU - Lada, Steven

AU - Estes, Jacob

AU - Fletcher, Courtney V.

AU - Podany, Anthony T.

AU - Anderson, Jodi

AU - Schmidt, Thomas

AU - Wietgrefe, Steve

AU - Schacker, Timothy

AU - Verneris, Michael R.

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N2 - Background. Allogeneic hematopoietic cell transplantation (allo-HCT) in a CCR5∆32 homozygous donor resulted in HIV cure. Understanding how allo-HCT impacts the HIV reservoir will inform cure strategies. Methods. A 12-year-old with perinatally acquired, CCR5-tropic HIV and acute lymphoblastic leukemia underwent myeloablative conditioning and umbilical cord blood (UCB) transplantation from a CCR5∆32 homozygous donor. Peripheral blood mononuclear cells (PBMCs) and the rectum were sampled pre- and post-transplant. The brain, lung, lymph node (LN), stomach, duodenum, ileum, and colon were sampled 73 days after transplantation (day +73), when the patient died from graft-vs-host disease. Droplet digital polymerase chain reaction (ddPCR) and in situ hybridization (ISH) were used detect the HIV reservoir in tissues. CCR5 and CD3 expression in the LN was assessed using immunohistochemistry (IHC). Results. HIV DNA (vDNA) was detected in PBMCs by ddPCR pretransplant but not post-transplant. vDNA was detected by ISH in the rectum at days -8 and +22, and in the LN, colon, lung, and brain day +73. vDNA was also detected in the lung by ddPCR. IHC revealed CCR5+CD3+ cells in the LN postmortem. Conclusions. HIV was detected in multiple tissues 73 days after CCR5∆32 homozygous UCB allo-HCT despite myeloablative conditioning and complete donor marrow engraftment. These results highlight the importance of analyzing tissue during HIV cure interventions and inform the choice of assay used to detect HIV in tissue reservoirs.

AB - Background. Allogeneic hematopoietic cell transplantation (allo-HCT) in a CCR5∆32 homozygous donor resulted in HIV cure. Understanding how allo-HCT impacts the HIV reservoir will inform cure strategies. Methods. A 12-year-old with perinatally acquired, CCR5-tropic HIV and acute lymphoblastic leukemia underwent myeloablative conditioning and umbilical cord blood (UCB) transplantation from a CCR5∆32 homozygous donor. Peripheral blood mononuclear cells (PBMCs) and the rectum were sampled pre- and post-transplant. The brain, lung, lymph node (LN), stomach, duodenum, ileum, and colon were sampled 73 days after transplantation (day +73), when the patient died from graft-vs-host disease. Droplet digital polymerase chain reaction (ddPCR) and in situ hybridization (ISH) were used detect the HIV reservoir in tissues. CCR5 and CD3 expression in the LN was assessed using immunohistochemistry (IHC). Results. HIV DNA (vDNA) was detected in PBMCs by ddPCR pretransplant but not post-transplant. vDNA was detected by ISH in the rectum at days -8 and +22, and in the LN, colon, lung, and brain day +73. vDNA was also detected in the lung by ddPCR. IHC revealed CCR5+CD3+ cells in the LN postmortem. Conclusions. HIV was detected in multiple tissues 73 days after CCR5∆32 homozygous UCB allo-HCT despite myeloablative conditioning and complete donor marrow engraftment. These results highlight the importance of analyzing tissue during HIV cure interventions and inform the choice of assay used to detect HIV in tissue reservoirs.

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KW - CCR5∆32

KW - HIV cure

KW - HIV reservoirs

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DO - 10.1093/ofid/ofy090

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