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

Abstract

AbstractObjectiveAllogeneic 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.DesignWe 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.MethodsSHIV-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 α/β 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.ResultsThe 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SHIV-harboring cells persisted in lymphoid and non-lymphoid tissues, resulting in a rapid viral rebound in the ART-withdrawn MCM.ConclusionsOur results indicate that myeloablative conditioning and maintaining ART through the peri-transplant period alone are insufficient for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 α/β T cells are likely necessary to kill HIV latently infected cells following allo-HSCTs.