Abstract
Background 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 but may include pre-transplant conditioning regimens, ART-mediated protection of donor cells, and graft-versus-host (GvH) responses. 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.
Results We infected four MCMs with CCR5-tropic SHIV162P3 and started ART 6-16 weeks post-infection (p.i.) to establish robust viral reservoirs. We maintained the MCMs on continuous ART during myeloablative conditioning with total body irradiation (TBI) and while transplanting allogeneic MHC-matched α/β T cell-depleted bone marrow cells. Post-transplant, we prophylactically treated the MCMs with cyclophosphamide and tacrolimus to prevent GvH disease (GvHD). The transplants produced ~85% whole blood donor chimerism without causing high-grade GvHD. Consequently, three MCMs had undetectable SHIV DNA in their peripheral blood mononuclear cells post-transplant. However, SHIV-harboring cells persisted in various tissues. We detected viral DNA in lymph node biopsies and terminal analyses of tissues between 38 and 62 days post-transplant. Further, we removed ART from one MCM at 63 days post-transplant, resulting in viral rebound within seven days and viral loads nearing 1×108 SHIV RNA copies/ml of plasma after treatment interruption.
Conclusions Our results indicate that myeloablative conditioning and maintaining ART through the peri-transplant period alone are insufficient for eradicating latent viral reservoirs early after allo-HSCTs. Furthermore, our findings suggest that extended ART and GvH responses may be necessary to substantially deplete viral reservoirs after allo-HSCTs.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵** Matthew R. Reynolds and Igor I. Slukvin should be considered co-senior authors.
Abbreviations
- Allo-HSCTs
- Allogeneic hematopoietic stem cell transplants
- ART
- Antiretroviral therapy
- HIV
- Human immunodeficiency virus
- SHIV
- Simian-human immunodeficiency virus
- MCMs
- Mauritian cynomolgus macaques
- GvH
- Graft-versus-host
- GvHD
- Graft-versus-host disease
- GvVR
- Graft-versus-viral reservoir
- CCR5
- C-C chemokine receptor type 5
- CXCR4
- C-X-C chemokine receptor type 4
- CCR5Δ32
- C-C chemokine receptor type 5 with 32 base-pair deletion
- MHC
- Major histocompatibility complex
- NHPs
- Nonhuman primates
- BM
- Bone marrow
- p.i.
- Post-infection
- Gy
- Gray
- WBCs
- White blood cells
- ATIs
- Analytical treatment interruptions
- DLIs
- Donor lymphocyte infusions
- CAR
- Chimeric antigen receptor
- mHAgs
- Minor histocompatibility antigens
- WNPRC
- Wisconsin national primate research center
- gDNA
- Genomic deoxyribonucleic acid
- PCRs
- Polymerase chain reactions
- Mafa
- Macaca fascicularis
- TCID50
- Median tissue culture infectious doses
- qRT-PCRs
- Quantitative real-time polymerase chain reactions
- cDNA
- Complementary deoxyribonucleic acid
- PMPA
- Tenofovir (9-[9(R)-2-(phosphonomethoxy)propyl]adenine
- FTC
- Emtricitabine
- RAL
- Raltegravir
- SFEM
- Serum-free expansion medium
- TBI
- Total body irradiation
- SCF
- Stem cell factor
- FLT3
- Fms-related tyrosine kinase 3
- TPO
- Thrombopoietin
- PBMCs
- Peripheral blood mononuclear cells
- SNPs
- Single-nucleotide polymorphisms
- vDNA
- viral deoxyribonucleic acids
- ddPCR
- Digital droplet polymerase chain reaction
- RPP30
- RNase P subunit p30