RT Journal Article
SR Electronic
T1 MHC-matched allogeneic bone marrow transplant fails to eliminate SHIV-infected cells from ART-suppressed Mauritian cynomolgus macaques
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.04.16.440168
DO 10.1101/2021.04.16.440168
A1 Jason T. Weinfurter
A1 Saritha S. D’Souza
A1 Lea M. Matschke
A1 Sarah Bennett
A1 Laurel E. Kelnhofer-Millevolte
A1 Kran Suknuntha
A1 Akhilesh Kumar
A1 Jennifer Coonen
A1 Christian M. Capitini
A1 Peiman Hematti
A1 Thaddeus G. Golos
A1 Igor I. Slukvin
A1 Matthew R. Reynolds
YR 2021
UL http://biorxiv.org/content/early/2021/04/16/2021.04.16.440168.abstract
AB 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 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.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SHIV-harboring cells persisted in lymphoid and non-lymphoid tissues, resulting in a rapid viral rebound in the ART-withdrawn MCM.Conclusions Our results indicate that myeloablative conditioning and maintaining ART through the peri-transplant period alone are insufficient for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 α/β T cells are likely necessary to kill HIV latently infected cells following allo-HSCTs.Competing Interest StatementThe authors have declared no competing interest.