TY - JOUR
T1 - Mechanisms that contribute to a profound reduction of the HIV-1 reservoir after allogeneic stem cell transplant
AU - Salgado, Maria
AU - Kwon, Mi
AU - Gálvez, Cristina
AU - Badiola, Jon
AU - Nijhuis, Monique
AU - Bandera, Alessandra
AU - Balsalobre, Pascual
AU - Miralles, Pilar
AU - Buño, Ismael
AU - Martinez-Laperche, Carolina
AU - Vilaplana, Cristina
AU - Jurado, Manuel
AU - Clotet, Bonaventura
AU - Wensing, Annemarie
AU - Martinez-Picado, Javier
AU - Diez-Martin, Jose Luis
N1 - Funding Information:
This study was supported by the Foundation for AIDS Research (amfAR) through the amfAR Research Consortium on HIV Eradication (ARCHE) program (grants 108930-56-RGRL, 109293-59-RGRL, and 109552-61-RGRL) as well as Dutch Aidsfonds grants 2013034 and 2016026. Ms. Gálvez was supported by the PhD fellowship of the Spanish Ministry of Education, Culture and Sport (FPU15/03698). The funding sources had no role in the design or conduct of the study or the decision to submit the manuscript for publication.
Funding Information:
Grant Support: This study was supported by amfAR through the ARCHE program (grants 108930-56-RGRL, 109293-59-RGRL, and 109552-61-RGRL) and by Dutch Aidsfonds grants 2013034 and 2016026. Ms. Gálvez was supported by the PhD fellowship of the Spanish Ministry of Education, Culture and Sport (FPU15/03698).
Publisher Copyright:
© 2018 American College of Physicians.
PY - 2018/11/20
Y1 - 2018/11/20
N2 - Background: The multifactorial mechanisms associated with radical reductions in HIV-1 reservoirs after allogeneic hematopoietic stem cell transplant (allo-HSCT), including a case of HIV cure, are not fully understood. Objective: To investigate the mechanism of HIV-1 eradication associated with allo-HSCT. Design: Nested case series within the IciStem observational cohort. Setting: Multicenter European study. Participants: 6 HIV-infected, antiretroviral-treated participants who survived more than 2 years after allo-HSCT with CCR5 wildtype donor cells. Measurements: HIV DNA analysis, HIV RNA analysis, and quantitative viral outgrowth assay were performed in blood, and HIV DNA was also measured in lymph nodes, ilea, bone marrow, and cerebrospinal fluid. A humanized mouse model was used for in vivo detection of the replication-competent blood cell reservoir. HIV-specific antibodies were measured in plasma. Results: Analysis of the viral reservoir showed that 5 of 6 participants had full donor chimera in T cells within the first year after transplant, undetectable proviral HIV DNA in blood and tissue, and undetectable replication-competent virus (<0.006 infectious unit per million cells). The only participant with detectable virus received cord blood stem cells with an antithymocyte globulin- containing conditioning regimen, did not develop graft-versushost disease, and had delayed complete standard chimerism in T cells (18 months) with mixed ultrasensitive chimera. Adoptive transfer of peripheral CD4+ T cells to immunosuppressed mice resulted in no viral rebound. HIV antibody levels decreased over time, with 1 case of seroreversion. Limitation: Few participants. Conclusion: Allo-HSCT resulted in a profound long-term reduction in the HIV reservoir. Such factors as stem cell source, conditioning, and a possible "graft-versus-HIV-reservoir" effect may have contributed. Understanding the mechanisms involved in HIV eradication after allo-HSCT can enable design of new curative strategies.
AB - Background: The multifactorial mechanisms associated with radical reductions in HIV-1 reservoirs after allogeneic hematopoietic stem cell transplant (allo-HSCT), including a case of HIV cure, are not fully understood. Objective: To investigate the mechanism of HIV-1 eradication associated with allo-HSCT. Design: Nested case series within the IciStem observational cohort. Setting: Multicenter European study. Participants: 6 HIV-infected, antiretroviral-treated participants who survived more than 2 years after allo-HSCT with CCR5 wildtype donor cells. Measurements: HIV DNA analysis, HIV RNA analysis, and quantitative viral outgrowth assay were performed in blood, and HIV DNA was also measured in lymph nodes, ilea, bone marrow, and cerebrospinal fluid. A humanized mouse model was used for in vivo detection of the replication-competent blood cell reservoir. HIV-specific antibodies were measured in plasma. Results: Analysis of the viral reservoir showed that 5 of 6 participants had full donor chimera in T cells within the first year after transplant, undetectable proviral HIV DNA in blood and tissue, and undetectable replication-competent virus (<0.006 infectious unit per million cells). The only participant with detectable virus received cord blood stem cells with an antithymocyte globulin- containing conditioning regimen, did not develop graft-versushost disease, and had delayed complete standard chimerism in T cells (18 months) with mixed ultrasensitive chimera. Adoptive transfer of peripheral CD4+ T cells to immunosuppressed mice resulted in no viral rebound. HIV antibody levels decreased over time, with 1 case of seroreversion. Limitation: Few participants. Conclusion: Allo-HSCT resulted in a profound long-term reduction in the HIV reservoir. Such factors as stem cell source, conditioning, and a possible "graft-versus-HIV-reservoir" effect may have contributed. Understanding the mechanisms involved in HIV eradication after allo-HSCT can enable design of new curative strategies.
KW - Adoptive Transfer
KW - Adult
KW - Animals
KW - Anti-HIV Agents/therapeutic use
KW - CD4 Antigens/immunology
KW - Case-Control Studies
KW - DNA, Viral/analysis
KW - Follow-Up Studies
KW - HIV Antibodies/blood
KW - HIV Infections/complications
KW - HIV-1/genetics
KW - Hematologic Diseases/complications
KW - Hematopoietic Stem Cell Transplantation/methods
KW - Humans
KW - Immunity, Humoral
KW - Male
KW - Mice
KW - Models, Animal
KW - RNA, Viral/analysis
KW - Transplantation Chimera
KW - Transplantation, Homologous
KW - Viral Load
KW - Young Adult
UR - https://www.scopus.com/pages/publications/85056708038
U2 - 10.7326/M18-0759
DO - 10.7326/M18-0759
M3 - Article
C2 - 30326031
AN - SCOPUS:85056708038
SN - 0003-4819
VL - 169
SP - 674
EP - 683
JO - Annals of Internal Medicine
JF - Annals of Internal Medicine
IS - 10
ER -