Allogeneic MHC-matched T-cell receptor α/β-depleted bone marrow transplants in SHIV-infected, ART-suppressed Mauritian cynomolgus macaques

Jason T. Weinfurter, Saritha S. D’Souza, Lea M. Matschke, Sarah Bennett, Laurel E. Kelnhofer-Millevolte, Kran Suknuntha, Akhilesh Kumar, Jennifer Coonen, Christian M. Capitini, Peiman Hematti, Thaddeus G. Golos, Igor I. Slukvin, Matthew R. Reynolds

Research output: Contribution to journalArticlepeer-review

Abstract

Allogeneic hematopoietic stem cell transplants (allo-HSCTs) dramatically reduce HIV reservoirs in antiretroviral therapy (ART) suppressed individuals. However, the mechanism(s) responsible for these post-transplant viral reservoir declines are not fully understood. Therefore, we modeled allo-HSCT in ART-suppressed simian-human immunodeficiency virus (SHIV)-infected Mauritian cynomolgus macaques (MCMs) to illuminate factors contributing to transplant-induced viral reservoir decay. Thus, we infected four MCMs with CCR5-tropic SHIV162P3 and started them on ART 6–16 weeks post-infection (p.i.), maintaining continuous ART during myeloablative conditioning. To prevent graft-versus-host disease (GvHD), we transplanted allogeneic MHC-matched α/β T cell-depleted bone marrow cells and prophylactically treated the MCMs with cyclophosphamide and tacrolimus. The transplants produced ~ 85% whole blood donor chimerism without causing high-grade GvHD. Consequently, three MCMs had undetectable SHIV DNA in their blood post-transplant. However, SHIV-harboring cells persisted in various tissues, with detectable viral DNA in lymph nodes and tissues between 38 and 62 days post-transplant. Further, removing one MCM from ART at 63 days post-transplant resulted in SHIV rapidly rebounding within 7 days of treatment withdrawal. In conclusion, transplanting SHIV-infected MCMs with allogeneic MHC-matched α/β T cell-depleted bone marrow cells prevented high-grade GvHD and decreased SHIV-harboring cells in the blood post-transplant but did not eliminate viral reservoirs in tissues.

Original languageEnglish (US)
Article number12345
JournalScientific reports
Volume12
Issue number1
DOIs
StatePublished - Dec 2022

Bibliographical note

Funding Information:
This study was funded by the National Institutes of Health (NIH) via grants R24 OD021322 awarded to I.I.S., T.G., and M.R.R. Additional support was provided by the Office of Research Infrastructure Programs/ OD via grant P51 OD011106 awarded to the WNPRC at the University of Wisconsin-Madison, and by St. Baldrick's-Stand up to Cancer Dream Team Translational Research Grant SU2C-AACR-DT-27-17 to C.M.C and P.H., NIH/National Cancer Institute (NCI) Grant K08 CA174750 and NIH/NCI Grant R01 CA215461 to C.M.C.

Publisher Copyright:
© 2022, The Author(s).

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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