Abstract
The conditioning regimen used as part of the Berlin patient’s hematopoietic cell transplant likely contributed to his eradication of HIV infection. We studied the impact of conditioning in simian-human immunodeficiency virus–infected (SHIV-infected) macaques suppressed by combination antiretroviral therapy (cART). The conditioning regimen resulted in a dramatic, but incomplete depletion of CD4+ and CD8+ T cells and CD20+ B cells, increased T cell activation and exhaustion, and a significant loss of SHIV-specific Abs. The disrupted T cell homeostasis and markers of microbial translocation positively correlated with an increased viral rebound after cART interruption. Quantitative viral outgrowth and Tat/rev–induced limiting dilution assays showed that the size of the latent SHIV reservoir did not correlate with viral rebound. These findings identify perturbations of the immune system as a mechanism for the failure of autologous transplantation to eradicate HIV. Thus, transplantation strategies may be improved by incorporating immune modulators to prevent disrupted homeostasis, and gene therapy to protect transplanted cells.
| Original language | English (US) |
|---|---|
| Article number | e91230 |
| Journal | JCI Insight |
| Volume | 2 |
| Issue number | 4 |
| DOIs | |
| State | Published - Feb 23 2017 |
Bibliographical note
Funding Information:This study was supported by grants from the NIH National Institute of Allergy and Infectious Diseases (U19 AI096111 and UM1 AI126623 to HPK and KRJ) and National Heart, Lung, and Blood Institute (R01 HL116217 and U19 HL129902 to HPK). This study was also supported by NIH P51 OD010425 and UW/FHCRC CFAR AI027757. HPK is a Markey Molecular Medicine Investigator and received support as the inaugural recipient of the José Carreras/E. Donnall Thomas Endowed Chair for Cancer Research and the Fred Hutch Endowed Chair for Cell and Gene Therapy.
Funding Information:
The authors thank Helen Crawford for help in preparing this manuscript; Veronica Nelson, Erica Curry, and Kelvin Sze for outstanding support in our pigtail macaque studies; Andrea Repetto, and Sowmya Reddy for processing of macaque samples; and Joel Ahrens for assistance with sample collections. We also thank Tae-Wook Chun for his expertise and support in development of the macaque-adapted quantitative viral outgrowth assay. This study was supported by grants from the NIH National Institute of Allergy and Infectious Diseases (U19 AI096111 and UM1 AI126623 to HPK and KRJ) and National Heart, Lung, and Blood Institute (R01 HL116217 and U19 HL129902 to HPK). This study was also supported by NIH P51 OD010425 and UW/FHCRC CFAR AI027757. HPK is a Markey Molecular Medicine Investigator and received support as the inaugural recipient of the Jos? Carreras/E. Donnall Thomas Endowed Chair for Cancer Research and the Fred Hutch Endowed Chair for Cell and Gene Therapy.
Publisher Copyright:
© 2017 American Society for Clinical Investigation. All rights reserved.
UN SDGs
This output contributes to the following UN Sustainable Development Goals (SDGs)
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SDG 3 Good Health and Well-being
Keywords
- Animals
- Anti-Retroviral Agents/therapeutic use
- CD4-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/immunology
- HIV Infections/drug therapy
- HIV-1/radiation effects
- Hematopoietic Stem Cell Transplantation/methods
- Homeostasis/radiation effects
- Lentivirus Infections/drug therapy
- Macaca nemestrina
- Simian Acquired Immunodeficiency Syndrome/drug therapy
- Simian Immunodeficiency Virus/radiation effects
- Transplantation Conditioning/methods
- Transplantation, Autologous
- Viral Load/radiation effects
- Whole-Body Irradiation
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
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