(1.6)--Nature-伦敦病人1.pdf
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1、Letterhttps:/doi.org/10.1038/s41586-019-1027-4HIV-1 remission following CCR532/32 haematopoietic stem-cell transplantationA cure for HIV-1 remains unattainable as only one case has been reported,a decade ago1,2.The individualwho is known as the Berlin patientunderwent two allogeneic haematopoietic s
2、tem-cell transplantation(HSCT)procedures using a donor with a homozygous mutation in the HIV coreceptor CCR5(CCR532/32)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-ter
3、m 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 Hodgkins lymphoma using cells from a CCR532/32 donor.He experienced mild gut graft-versus-host disease.Antiretroviral therapy was int
4、errupted 16months after transplantation.HIV-1 remission has been maintained over a further 18months.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
5、lymphocytes show no reactivatable virus using a total of 24million 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
6、 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 f
7、ollowing transplantation.Although at 18months 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 CCR532 donor cells may be sufficient to achieve HIV-1 remission with reduced intensity condi
8、tioning and no irradiation,and the findingsprovide further support forthe development of HIV-1 remission strategies based on preventing CCR5 expression.The HIV-1 epidemic continues and nearly 37million people are living with HIV-1 worldwide3.Although over 21million people with HIV-1 have access to l
9、ifelong antiretroviral therapy(ART)3,there is considerable drug-resistant HIV in both untreated4 and treated5,6 indi-viduals in low-and middle-income countries and sustainability of ART programmes is uncertain7.Drug-free durable HIV-1 suppression is therefore an urgent global priority.Thus far,the o
10、nly documented case of sustained HIV remission is the Berlin patient,who received two allogeneic HSCTs using cells from a homozygous CCR532(CCR532/32)donor1.This 32-base-pair deletion prevents CCR5 expression,rendering these cells resistant to infection with HIV variants that interact with the CCR5
11、coreceptor8.The only other case of a patient with HIV-1 who was transplanted with CCR532/32 cells and interrupted ART was the Essen patient9.In this case,ART was interrupted one week before allogeneic HSCT and rapid viral rebound of a pre-existing minority HIV-1 variant,which was able to infect cell
12、s through the alternative CXCR4 coreceptor,was observed three weeks later9,10.Such pre-existing CXCR4 variants were not observed in the Berlin patient11.Three other cases transplanted with wild-type CCR5 cells experienced viral rebound 12,32 or 41weeks after ART interruption despite a considerable r
13、eduction of the HIV reservoir12,13.We report an individual diagnosed with HIV-1 infection in 2003,with a CD4 nadir of 290cellsmm3 and a baseline HIV-1 plasma viral load of 180,000copies per ml.ART was initiated with tenofovir diso-proxil fumarate,emtricitabine and efavirenz in 2012.In December 2012,
14、the individual was diagnosed with stage IVb(nodular sclerosing)Hodgkins lymphoma.Hodgkins lymphoma was refractory to first-line chemotherapy(doxorubicin,bleomycin,vin-cristine and dacarbazine)and a number of salvage regimens,including etoposide,methylprednisolone,cytarabine and cisplatin;anti-CD30 m
15、onoclonal antibody(Brentuximab)and mini-LEAM(lomustine,etoposide,cytarabine and melphalan)were used.ART was switched to tenofovir disoproxil fumarate,emtricitabine and raltegravir during periods of chemotherapy for Hodgkins lymphoma;there was a 5-day episode of ART interruption in late 2015 with an
16、HIV-1 plasma viral load of 1,500copies per ml that did not reach the viral set point.On the basis of resistance mutations K65R and M184V in reverse transcriptase as well as E157Q in integrase,the regimen was switched to rilpivir-ine,lamivudine and dolutegravir;viral suppression was subsequently achi
17、eved.Mobilization of autologous peripheral blood stem cells failed despite the use of CXCR4 antagonists,thus precluding standard autologous HSCT.Complete metabolic remission as confirmed by computed tomography and positron-emission tomography criteria was achieved with ifosfamide,gemcitabineand vino
18、relbine(IGEV)chemotherapy in March 2016.An unrelated(nine out of ten)donor was identified from an interna-tional registry with one allelic mismatch at HLA-B by high-resolution HLA typing,who was CCR532/32(Extended Data Table1 and Methods).No fully matched donors were identified in the registry.The p
19、atient underwent conditioning with lomustine,cyclophosphamide,1Division of Infection and Immunity,UCL,London,UK.2Department of Infection,UCLH,London,UK.3Mortimer Market Centre,Department of HIV,CNWL NHS Trust,London,UK.4Department of Medicine,University of Cambridge,Cambridge,UK.5Africa Health Resea
20、rch Institute,Durban,South Africa.6Nuffield Department of Medicine,University of Oxford,Oxford,UK.7IrsiCaixa AIDS Research Institute,Badalona,Spain.8University of Vic Central University of Catalonia(UVic-UCC),Vic,Spain.9Catalan Institution for Research and Advanced Studies(ICREA),Barcelona,Spain.10T
21、ranslational Virology,Department of Medical Microbiology,University Medical Center,Utrecht,The Netherlands.11Department of Haematology,University of Cambridge,Cambridge,UK.12Department of Virology,UCLH,London,UK.13Department of Haematology,UCLH,London,UK.14Department of Clinical Haematology,Imperial
22、 College Healthcare NHS Trust,Hammersmith Hospital,London,UK.15Imperial College London,London,UK.16NIHR Oxford Biomedical Research Centre,Oxford,UK.17Department of Medicine,National University of Singapore,Singapore,Singapore.18Department of Haematology,Chelsea and Westminster Hospitals Foundation N
23、HS Trust,London,UK.19These authors contributed equally:Ian H.Gabriel,Eduardo Olavarria.*e-mail:rkg20cam.ac.uk2 4 4|N A t U r e|V O L 5 6 8|1 1 A P r I L 2 0 1 9Letter reSeArCHara-C and etoposide followed by infusion of 3.6106 CD34+cells per kg.In vivo T cell depletion was achieved by anti-CD52 antib
24、ody(alemtuzumab),10mg daily for 5days(days 7 to 3)before trans-plantation and graft-versus-host disease prophylaxis used cyclo-sporine-A with a short course of methotrexate.ART was continued throughout with rilpivirine,lamivudine and dolutegravir(Fig.1a).Allogeneic HSCT was relatively uncomplicated
25、and the patient was discharged on day31 after transplantation.Reactivation of both EpsteinBarr virus and cytomegalovirus(CMV)occurred at day85 after transplantation,requiring treatment with anti-CD20 monoclo-nal antibody(rituximab)and ganciclovir,respectively.At day77 after transplantation,the patie
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