HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-cell transplantation

Abstract

A cure for HIV-1 remains unattainable as only one case has been reported, a decade ago1,2. The individual—who is known as the ‘Berlin patient’—underwent two allogeneic haematopoietic stem-cell transplantation (HSCT) procedures using a donor with a homozygous mutation in the HIV coreceptor CCR5 (CCR5Δ32/Δ32) to treat his acute myeloid leukaemia. Total body irradiation was given with each HSCT. Notably, it is unclear which treatment or patient parameters contributed to this case of long-term HIV remission. Here we show that HIV-1 remission may be possible with a less aggressive and toxic approach. An adult infected with HIV-1 underwent allogeneic HSCT for Hodgkin’s lymphoma using cells from a CCR5Δ32/Δ32 donor. He experienced mild gut graft-versus-host disease. Antiretroviral therapy was interrupted 16 months after transplantation. HIV-1 remission has been maintained over a further 18 months. Plasma HIV-1 RNA has been undetectable at less than one copy per millilitre along with undetectable HIV-1 DNA in peripheral CD4 T lymphocytes. Quantitative viral outgrowth assays from peripheral CD4 T lymphocytes show no reactivatable virus using a total of 24 million resting CD4 T cells. CCR5-tropic, but not CXCR4-tropic, viruses were identified in HIV-1 DNA from CD4 T cells of the patient before the transplant. CD4 T cells isolated from peripheral blood after transplantation did not express CCR5 and were susceptible only to CXCR4-tropic virus ex vivo. HIV-1 Gag-specific CD4 and CD8 T cell responses were lost after transplantation, whereas cytomegalovirus-specific responses were detectable. Similarly, HIV-1-specific antibodies and avidities fell to levels comparable to those in the Berlin patient following transplantation. Although at 18 months after the interruption of treatment it is premature to conclude that this patient has been cured, these data suggest that a single allogeneic HSCT with homozygous CCR5Δ32 donor cells may be sufficient to achieve HIV-1 remission with reduced intensity conditioning and no irradiation, and the findings provide further support for the development of HIV-1 remission strategies based on preventing CCR5 expression.

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Fig. 1: Clinical course before and after allogeneic HSCT.
Fig. 2: Susceptibility of the CD4 T cells of the index patient to CCR5-tropic and CXCR4-tropic HIV-1 viruses and coreceptor usage by viruses before HSCT.
Fig. 3: HIV-specific antibodies.
Fig. 4: HIV-1 Gag-specific and CMV-specific T cell responses.

Data availability

SGA sequences are available via GenBank under accession numbers MK493056MK493075. Source Data are available for Figs. 14.

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Acknowledgements

This study was funded by a Wellcome Trust Senior Fellowship in Clinical Science to R.K.G., research capability funding (RCF) from UCLH BRC to R.K.G., as well as funding from Oxford and Cambridge Biomedical Research Centres (BRC), amfAR (The Foundation for AIDS Research), through the amfAR Research Consortium on HIV Eradication (ARCHE) program (AmfAR 109858-64-RSRL), the MRC (MR/R008698/1 to L.E.M. and MRM008614/2 to D.P.). A.J.I. is supported by an NIHR Clinical Lectureship, and acknowledges support from the NIHR and Imperial Biomedical Research Centre (BRC). E.N. received funding from the University College London Hospitals NHS Trust (UCLH)/University College London (UCL) National Institute for Health Research (NIHR) Biomedical Research Centre and research funding through an independent grant by ViiV Healthcare UK as part of the EPIICAL Consortium. We thank the CHERUB (http://www.cherub.uk.net) and IciStem Consortia (https://www.icistem.org/) for support and continuous discussion of results; N. Parmahand, M. Bandara, I. Jarvis, A. Fun, M. Lee, L. Hedley, K. Ardeshna, A. Hill, N. Goel, R. Szydlo, D. Slade, S. Griffith and C. Gálvez, Á. Hernández Rodríguez, V. González Soler and B. Rivaya Sánchez, E. van Maarseveen, L. Huyveneers, P. Schipper and D. de Jong; J. Apperley, Z. Allwood and S. Loaiza and all the nurses in the BMT Unit that looked after the patient.

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Nature thanks Steven Deeks, Sarah J. Fidler, Timothy Henrich and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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R.K.G., S.A.-J., S.G.E., E.O., H.P.M. and I.H.G. conceived and designed the study. S.A.-J., J.M.-P., A.M.J.W., M.S., M.N., F.S., L.M., I.H.G., L.E.M., D.P., H.P.M., P.G., E.N., A.M.L.L., L.W., S.G.E., M.P. and C.M. designed and/or performed experiments. R.K.G., J.M.-P., A.M.J.W., S.A.-J., M.S., M.N., F.S., L.M., L.E.M., E.O., H.L., J.F., M.P., I.H.G., H.P.M., S.G.E., E.N., P.G., J.L., A.J.I. and C.M. performed analyses and interpreted data. R.K.G., M.N., A.M.J.W., J.M.-P., A.M.L.L., J.L., H.P.M., and A.J.I. wrote the draft of the manuscript. J.M.-P., A.M.J.W., M.S., M.N., F.S., S.A.-J., L.M., L.E.M., D.P., H.P.M., P.G., E.N., A.M.L.L., S.G.E., L.W., M.P., I.H.G., H.P.M. and A.J.I. were involved in the critical revision of the manuscript for important intellectual content.

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Correspondence to Ravindra K. Gupta.

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Extended data figures and tables

Extended Data Fig. 1 Blood cell populations over time.

3TC, lamivudine; CsA, cyclosporine-A; DTG, dolutegravir; RPV, rilpivirine; WBC, white blood cells.

Extended Data Fig. 2 Susceptibility of CD4 T cells from the index patient to CCR5-tropic and CXCR4-tropic HIV-1.

a, Experimental flow for measurement of infection by intracellular p24 Gag staining. Control cells were from a healthy HIVCCR5 donor. b, Flow cytometry analysis of PBMCs following three days of stimulation exhibiting the expression pattern of CCR5 receptor within CD3 CD4 T cells in both healthy donor (control) and index patient. c. Culture supernatants from CD4 T cells infected with CCR5- and CXCR4-tropic viruses were collected on days three and seven to measure infectivity on HeLa TZM-bl reporter cells. Infectivity is measured as a reduction in the gene expression of the Tat-induced firefly luciferase reporter in TZM-bl cells. data are mean ±s.e.m. n = 2: one donor and one index patient. Experiments were repeated three times with similar results.

Extended Data Fig. 3 CD8 T cell responses and CD4 T cell responses to HIV.

Representative fluorescence-activated cell sorting plots showing the percentage of virus-specific CD8 T cells (top) and CD4 T cells (bottom) identified by intracellular staining for IFNγ, following stimulation with HIV Pol, Env and Nef peptide pools after HSCT at days 96 and 819.

Extended Data Table 1 Comparison of blood group and tissue type between stem cell donor and index case
Extended Data Table 2 Detection of bands on western blot pre- and post-transplantation

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Gupta, R.K., Abdul-Jawad, S., McCoy, L.E. et al. HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-cell transplantation. Nature 568, 244–248 (2019). https://doi.org/10.1038/s41586-019-1027-4

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