Maria Salgado, PhD *; Mi Kwon, MD *; Cristina Gálvez, MS; Jon Badiola, MD; Monique Nijhuis, PhD; Alessandra Bandera, MD, PhD; Pascual Balsalobre, PhD; Pilar Miralles, MD; Ismael Buño, PhD; Carolina Martinez-Laperche, PhD; Cristina Vilaplana, MD, PhD; Manuel Jurado, MD, PhD; Bonaventura Clotet, MD, PhD; Annemarie Wensing, MD; Javier Martinez-Picado, PhD †; Jose Luis Diez-Martin, MD, PhD †; for the IciStem Consortium ‡
Acknowledgment: The authors thank the members of the IciStem Consortium (see the Appendix) for their support and discussion of the results. The authors also thank Jeffrey Laurence for his critical review and helpful comments, as well as Marco A. Fernández Sanmartín from the Flow Cytometry Service of the Institut de Recerca Germans Trias i Pujol; Águeda Hernández Rodríguez, Victoria González Soler, and Belén Rivaya Sánchez from the Microbiology Department of the Hospital Universitari Germans Trias i Pujol; and Jorge Díaz Pedroza, Yaiza Salgado, and Pere-Joan Cardona i Iglesias from the Institut de Recerca Germans Trias i Pujol animal facility. Finally, the authors acknowledge Joel Blankson for his help in the development of the mouse VOA protocol.
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).
Disclosures: Dr. Wensing reports grants and consultancy fees from ViiV Healthcare, Gilead, Janssen, Merck, CLJI, and Virology Education outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M18-0759.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Proctor & Gamble, Pfizer, and Johnson & Johnson.
Reproducible Research Statement:Study protocol, statistical code, and data set: Specific aspects will be made available to approved persons through written agreements with the principal investigators of the IciStem Consortium (e-mail, firstname.lastname@example.org).
Corresponding Author: Javier Martinez-Picado, PhD, IrsiCaixa AIDS Research Institute, Hospital Germans Trias i Pujol, Carretera de Canyet, s/n, 08916 Badalona, Barcelona, Spain; e-mail, email@example.com.
Current Author Addresses: Drs. Salgado, Clotet, and Martinez-Picado and Ms. Gálvez: IrsiCaixa AIDS Research Institute, Hospital Germans Trias i Pujol, Carretera de Canyet, s/n, 08916 Badalona, Barcelona, Spain.
Drs. Kwon, Balsalobre, Buño, Martinez-Laperche, and Diez-Martin: Hematology Department, Gregorio Marañón G. University Hospital, Gregorio Marañón Health Research Institute, Dr Esquerdo 46, 28007 Madrid, Spain.
Drs. Badiola and Jurado: Virgen de las Nieves University Hospital, Avenida de las Fuerzas Armadas, 2, 18014 Granada, Spain.
Drs. Nijhuis and Wensing: Department of Medical Microbiology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands.
Dr. Bandera: San Gerardo Hospital, University of Milano-Bicocca, Via Pergolesi, 33, 20900 Monza, Italy.
Dr. Miralles: Microbiology and Infectious Diseases Department, Gregorio Marañón G. University Hospital, Gregorio Marañón Health Research Institute, Calle de Máiquez, 7, 28009 Madrid, Spain.
Dr. Vilaplana: Germans Trias i Pujol Research Institute, Can Ruti Campus, Carretera de Can Ruti, Camí de les Escoles, s/n, 08916 Badalona, Spain.
Author Contributions: Conception and design: M. Salgado, M. Kwon, M. Nijhuis, P. Balsalobre, B. Clotet, A. Wensing, J. Martinez-Picado, J.L. Diez-Martin.
Analysis and interpretation of the data: M. Salgado, M. Kwon, C. Gálvez, M. Nijhuis, A. Bandera, P. Balsalobre, P. Miralles, I. Buño, C. Martinez-Laperche, C. Vilaplana, B. Clotet, A. Wensing, J. Martinez-Picado, J.L. Diez-Martin.
Drafting of the article: M. Salgado, M. Kwon, P. Balsalobre, J. Martinez-Picado, J.L. Diez-Martin.
Critical revision of the article for important intellectual content: M. Salgado, M. Kwon, J. Badiola, A. Bandera, P. Balsalobre, P. Miralles, I. Buño, C. Martinez-Laperche, B. Clotet, A. Wensing, J. Martinez-Picado, J.L. Diez-Martin.
Final approval of the article: M. Salgado, M. Kwon, C. Gálvez, J. Badiola, M. Nijhuis, A. Bandera, P. Balsalobre, P. Miralles, I. Buño, C. Martinez-Laperche, C. Vilaplana, M. Jurado, B. Clotet, A. Wensing, J. Martinez-Picado, J.L. Diez-Martin.
Provision of study materials or patients: M. Salgado, M. Kwon, J. Badiola, A. Bandera, P. Balsalobre, P. Miralles, C. Martinez-Laperche, C. Vilaplana, M. Jurado, B. Clotet, J.L. Diez-Martin.
Obtaining of funding: M. Salgado, M. Nijhuis, P. Balsalobre, B. Clotet, A. Wensing, J. Martinez-Picado.
Administrative, technical, or logistic support: P. Balsalobre.
Collection and assembly of data: M. Salgado, M. Kwon, C. Gálvez, J. Badiola, M. Nijhuis, A. Bandera, P. Balsalobre, P. Miralles, I. Buño, C. Martinez-Laperche, C. Vilaplana, M. Jurado, A. Wensing, J. Martinez-Picado, J.L. Diez-Martin.
This article has been corrected. The original version (PDF) is appended to this article as a Supplement.
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.
To investigate the mechanism of HIV-1 eradication associated with allo-HSCT.
Nested case series within the IciStem observational cohort.
Multicenter European study.
6 HIV-infected, antiretroviral-treated participants who survived more than 2 years after allo-HSCT with CCR5 wild-type donor cells.
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.
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-versus-host 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.
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.
The Foundation for AIDS Research (amfAR).
Appendix Table. HIV Latent Reservoir in Blood and Tissues in All Samples Isolated From Each Patient*
Gating strategy to quantify engraftment of human cells (proportion of human CD45+ cells), CD4 (defined as CD3+CD8−) cell activation, and the event of any CD8 or NK contamination.
NK = natural killer.
Table. Clinical, Hematologic, and Virologic Characteristics of the 6 Patients
HIV reservoirs measured in blood and tissues after transplant.
Data are from the last collected sample for each patient. Open symbols represent undetectable values (only IciS-01 had detectable values). In those cases, the limit of detection for the sample varied on the basis of cell/volume input, and that value is represented. CSF = cerebrospinal fluid; qVOA = quantitative viral outgrowth assay; Tfh = T-follicular helper cells; usVL = ultrasensitive viral load.
Relationship between latency parameters measured in each participant and clinical conditions of each allogeneic stem cell transplant.
ND = not determined; PBPC = peripheral blood progenitor cells.
* Full donor chimera within a month.
Peripheral blood standard donor chimerism, proviral HIV DNA, and plasma HIV RNA evolution after transplant in IciS-06.
Open diamonds and circles indicate undetectable HIV RNA (ultrasensitive viral load) and proviral HIV DNA, respectively, and represent the limit of detection of each technique, which is based on cell/plasma input. For chimerism expressed as percentage of donor cells, open squares indicate full donor chimera. GvHD = graft-versus-host disease.
Western blot analysis from the 6 analyzed patients.
Gray arrows indicate bands left or reduced intensity in each case.
HIV-specific antibody determination using the VITROS enzyme immunoassay.
A. Absolute antibody quantification in the last sample from each transplant recipient compared with viremic and treated HIV-positive patients and HIV-negative donors. B. Detuned low-sensitivity antibody quantification in the last sample from each transplant recipient compared with viremic and treated HIV-positive patients and HIV-negative donors. C. Absolute antibody quantification in longitudinal plasma samples from all included patients. D. Detuned low-sensitivity antibody quantification in all included patients.
In vivo mouse viral rebound model.
All 6 patients had undetectable values. Open symbols represent undetectable values. Limit of detection relative to plasma volume input is shown. Error bars represent medians and interquartile ranges of the values from the 5 mice used for each patient. allo-HSCT = allogeneic hematopoietic stem cell transplant; cART = combination antiretroviral therapy; ddPCR = droplet digital polymerase chain reaction; wt = wild-type.
Activation profiles of CD4+ T cells from each mouse infused with human cells from each of the studied patients.
Activation is measured as expression of HLA-DR, CD25, and CD69 together.
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In this video, Maria Salgado, PhD, and Javier Martinez-Picado, PhD, offer additional insight into the article, "Mechanisms That Contribute to a Profound Reduction of the HIV-1 Reservoir After Allogeneic Stem Cell Transplant."
Salgado M, Kwon M, Gálvez C, et al, for the IciStem Consortium. Mechanisms That Contribute to a Profound Reduction of the HIV-1 Reservoir After Allogeneic Stem Cell Transplant. Ann Intern Med. 2018;169:674–683. [Epub ahead of print 16 October 2018]. doi: 10.7326/M18-0759
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Published: Ann Intern Med. 2018;169(10):674-683.
Published at www.annals.org on 16 October 2018
HIV, Infectious Disease.
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