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MHC-matched allogeneic bone marrow transplant fails to eliminate SHIV-infected cells from ART-suppressed Mauritian cynomolgus macaques

By 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

Posted 16 Apr 2021
bioRxiv DOI: 10.1101/2021.04.16.440168

Objective: Allogeneic hematopoietic stem cell transplants (allo-HSCTs) in antiretroviral therapy (ART) suppressed individuals can significantly reduce human immunodeficiency virus (HIV) latent reservoirs and lead to prolonged ART-free remission. The mechanisms reducing the reservoir size are not fully understood but may include pre-transplant conditioning regimens, ART-mediated protection of donor cells, and graft-versus-host responses. Design: We modeled allo-HSCT in four ART-suppressed simian-human immunodeficiency virus (SHIV)-infected Mauritian cynomolgus macaques (MCMs) to examine the role of transplant mediated factors in eliminating SHIV latently infected cells. Methods: SHIV-infected MCMs started ART 6-16 weeks post-infection. After 3-6 weeks on ART, the MCMs received myeloablative conditioning and MHC-matched bone marrow depleted of /{beta} T cells. The MCMs were treated with GvH disease (GvHD) prophylaxis consisting of cyclophosphamide and tacrolimus and maintained daily ART post-transplant. One MCM was removed from ART 74 days post-transplant, while the remaining three MCMs continued ART until their necropsies. Viral reservoirs were measured in the peripheral blood and lymph nodes pre- and post-transplant and tissues at necropsy. Results: The treatment regimen induced profound lymphocyte depletion without causing severe GvHD, producing undetectable viral loads post-transplant. However, SHIV-harboring cells persisted in lymphoid and non-lymphoid tissues, resulting in a rapid viral rebound in the ART withdrawn MCM. Conclusions: Our results indicate that myeloablative conditioning and maintaining ART through the peri-transplant period alone are insufficient for eradicating latent reservoirs early after transplant. They also suggest that GvH responses mediated by /{beta} T cells are likely necessary to kill HIV latently infected cells following allo-HSCTs.

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