In-depth virological and immunological characterization of HIV-1 cure after CCR5Δ32/Δ32 allogeneic hematopoietic stem cell transplantation
Jensen, Björn Erik Ole; Knops, Elena; Cords, Leon; Lübke, Nadine; Salgado, Maria; Busman-Sahay, Kathleen; Estes, Jacob D.; Huyveneers, Laura E.P.; Perdomo-Celis, Federico; Wittner, Melanie; Gálvez, Cristina; Mummert, Christiane; Passaes, Caroline; Eberhard, Johanna M.; Münk, Carsten; Hauber, Ilona; Hauber, Joachim; Heger, Eva; De Clercq, Jozefien; Vandekerckhove, Linos; Bergmann, Silke; Dunay, Gábor A.; Klein, Florian; Häussinger, Dieter; Fischer, Johannes C.; Nachtkamp, Kathrin; Timm, Joerg; Kaiser, Rolf; Harrer, Thomas; Luedde, Tom; Nijhuis, Monique; Sáez-Cirión, Asier; Schulze zur Wiesch, Julian; Wensing, Annemarie M.J.; Martinez-Picado, Javier; Kobbe, Guido
(2023) Nature Medicine, volume 29, issue 3, pp. 583 - 587
(Article)
Abstract
Despite scientific evidence originating from two patients published to date that CCR5Δ32/Δ32 hematopoietic stem cell transplantation (HSCT) can cure human immunodeficiency virus type 1 (HIV-1), the knowledge of immunological and virological correlates of cure is limited. Here we characterize a case of long-term HIV-1 remission of a 53-year-old male who
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was carefully monitored for more than 9 years after allogeneic CCR5Δ32/Δ32 HSCT performed for acute myeloid leukemia. Despite sporadic traces of HIV-1 DNA detected by droplet digital PCR and in situ hybridization assays in peripheral T cell subsets and tissue-derived samples, repeated ex vivo quantitative and in vivo outgrowth assays in humanized mice did not reveal replication-competent virus. Low levels of immune activation and waning HIV-1-specific humoral and cellular immune responses indicated a lack of ongoing antigen production. Four years after analytical treatment interruption, the absence of a viral rebound and the lack of immunological correlates of HIV-1 antigen persistence are strong evidence for HIV-1 cure after CCR5Δ32/Δ32 HSCT.
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Keywords: General Biochemistry,Genetics and Molecular Biology, Journal Article
ISSN: 1078-8956
Publisher: Nature Research
Note: Funding Information: The IciStem program (www.icistem.org) is funded through the amfAR Research Consortium on HIV Eradication program (amfAR 109858-64-RSRL) and the Dutch Aidsfonds (P60802). University Hospital Düsseldorf was supported by the Heinz Ansmann Foundation for AIDS Research. The German Center for Infection Research (DZIF TTU 04.816, 04.819) supported University Hospital Cologne and the University Medical Center Hamburg-Eppendorf. J.S.z.W. Funding Information: The IciStem program ( www.icistem.org ) is funded through the amfAR Research Consortium on HIV Eradication program (amfAR 109858-64-RSRL) and the Dutch Aidsfonds (P60802). University Hospital Düsseldorf was supported by the Heinz Ansmann Foundation for AIDS Research. The German Center for Infection Research (DZIF TTU 04.816, 04.819) supported University Hospital Cologne and the University Medical Center Hamburg-Eppendorf. J.S.z.W. was supported by the European Research Council (ERC H2020 grant no. 681032), the H.W. & J. Hector Foundation (project no. M2101), the German Research Foundation (SFB1328 project A12) and Hamburg Investment and Development Bank (IFB Hamburg, PROFI no. 51167035). F.P.-C. was supported by Institut Pasteur’s Roux Cantarini program. T.H. and C. Mummert were supported by the German Research Foundation, Graduate School 1071, project B1. M.S. was given a grant by the Miguel Servet Fellowship (CP22/00038) and I+D+I RTI-A project (PID2020-115931RA-I00) from the Ministry of Science and Innovation. Research in the Martínez-Picado laboratory is supported by the Spanish Ministry of Science and Innovation (grant nos. PID2019-109870RB-I00 and CB21/13/00063), NIH/NIAID (1 UM1 AI164561-01), European Union HORIZON-HLTH-2021-DISEASE-04-07 (grant no. 101057100) and the Research Centers of Catalonia (grant no. 2017 SGR 252). C.G. was supported by the PhD fellowship of the Spanish Ministry of Education, Culture and Sport (FPU15/03698). J.D.E. and the Oregon National Primate Research Center were supported by the NIH/NIAID (grant no. R01AI143411) and the NIH/Office of the Director (grant no. P51OD011092), respectively. The funders had no role in the conceptualization, design, data collection, analysis, decision to publish or preparation of the paper. The authors thank IciStem no. 019 and all volunteers who participated in this study; K. Pohl, E. Bäcker, O. Adams, T. Feldt, F. Hüttig and N. Freise of University Hospital Düsseldorf for their assistance with patient care and/or sample logistics; S. Kummer and R. Woost of the University Medical Center Hamburg-Eppendorf for technical assistance with sample preparation and flow cytometry; M. Angin of Institut Pasteur for initial assistance with flow cytometry analyses; G. Hütter of Cellex, J. L. Diez Martin of Hospital Gregorio Marañón Madrid, J. Kuball, D. de Jong and M. van Luin of the University Medical Center Utrecht for contributing their expertise to the discussion; M. A. Fernandez Sanmartin, Flow Cytometry Service of the Institut de Recerca Germans Trias i Pujol for his contribution to the cytometry panel discussions and sample sorting; Á. Hernandez Rodrıguez, V. González Soler and B. Rivaya Sanchez of the Microbiology Department of the Hospital Universitari Germans Trias i Pujol for their assistance with the murine outgrowth assay and HIV antibodies; J. Diaz Pedroza and Y. Rosales of the Comparative Medicine and Bioimage Centre of Catalonia for their contribution to the development of the mVOA experiments; M. del Carmen García and I. González of the AIDS Research Institute IrsiCaixa for their assistance with the HIV-DNA ddPCR; J. Blankson of the Johns Hopkins University for his contribution to the development of the mVOA protocol; and the Oregon Health & Science University Knight BioLibrary for the lymph node sample. Funding Information: In the IFNγ ELISpot assay, 2 × 10 PBMCs per well were incubated for 40 h with HIV-1 peptides corresponding to known cytotoxic T lymphocyte (CTL) epitopes restricted by the patient’s HLA alleles (Supplementary Table ) at a final concentration of 6 μg ml. Concanavalin A and PHA (Sigma-Aldrich) served as positive controls. Peptides were either purchased from EMC Microcollections or kindly provided by the NIH AIDS Research and Reference Reagent Program or by the AIDS Reagent Project of the Medical Research Council and the European Community EVA Programme. 5 −1 Publisher Copyright: © 2023, The Author(s).
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