Timothy Brown remains in cART-free HIV remission following allogeneic hematopoietic stem cell transplant (HSCT), but attempts to recapitulate his cure have been unsuccessful. We recently established a nonhuman primate model of fully MHC-matched allogeneic HSCT to investigate the mechanism of cure in Timothy Brown. In this model, a reduced intensity conditioning (RIC) regimen consisting of chemotherapy, CD3 depletion, and total body irradiation (TBI) prior to HSCT results in durable, full multi-lineage donor chimerism in SIV-naïve HSCT recipients. Here, we sought to investigate (1) if similar results could be achieved without TBI, and (2) the impact of allogeneic HSCT on SIV reservoir size in cART-suppressed, SIV-infected recipients.
Allogeneic HSCT was performed with fully MHC-matched Mauritian cynomolgus macaque (MCM) donor-recipient pairs, including two fully cART-suppressed, SIV-infected recipients. Mobilized peripheral stem cells collected from donors by leukapheresis were transplanted into recipients following RIC with or without TBI. Donor engraftment was monitored by Illumina sequencing of single nucleotide polymorphisms. Immune subset reconstitution was assessed longitudinally by flow cytometric phenotyping and complete blood counts.
We performed two HSCTs without TBI, both resulting in low T cell donor chimerism (<15%). The first, SIV-naïve recipient experienced incomplete T cell rebound resulting in polyoma virus reactivation and euthanasia. The second, cART-suppressed, SIV-infected recipient stabilized post-HSCT, and experienced a reduction in lymph node-associated SIV DNA despite incomplete T cell donor chimerism. Adding back TBI for HSCT of a second cART-suppressed, SIV-infected recipient resulted in high levels of donor chimerism in whole blood (>95%) and T cells (~80%) within 30 days of HSCT (see figure). Subsequent donor lymphocyte infusion increased blood and tissue T cell donor chimerism levels to nearly 100%, but led to development of clinical graft-versus-host disease (GVHD) and euthanasia. At necropsy, SIV DNA was below the limit of detection in lymph nodes, constituting a ~3 log reduction from pre-HSCT levels.
These data demonstrate that TBI is critical to achieving high levels of T cell donor chimerism post-HSCT in MCM, and that while HSCT immune conditioning decreases the viral reservoir size, GVHD is associated with enhanced reservoir clearance. This model facilitates future studies of HSCT-mediated HIV cure.