TY - JOUR
T1 - Evidence for HIV-1 cure after CCR5Δ32/Δ32 allogeneic haemopoietic stem-cell transplantation 30 months post analytical treatment interruption
T2 - a case report
AU - Gupta, Ravindra Kumar
AU - Peppa, Dimitra
AU - Hill, Alison L.
AU - Gálvez, Cristina
AU - Salgado, Maria
AU - Pace, Matthew
AU - McCoy, Laura E.
AU - Griffith, Sarah A.
AU - Thornhill, John
AU - Alrubayyi, Aljawharah
AU - Huyveneers, Laura E.P.
AU - Nastouli, Eleni
AU - Grant, Paul
AU - Edwards, Simon G.
AU - Innes, Andrew J.
AU - Frater, John
AU - Nijhuis, Monique
AU - Wensing, Anne Marie J.
AU - Martinez-Picado, Javier
AU - Olavarria, Eduardo
N1 - Funding Information:
This study was funded by a Wellcome Trust Senior Fellowship in Clinical Science to RKG ( WT108082AIA ) and amfAR (American Foundation for AIDS Research), through the amfAR Research Consortium on HIV Eradication (ARCHE) programme (AmfAR 109858-64-RSRL). We also acknowledge funding from Oxford and Cambridge Biomedical Research Centres (BRCs) and the Medical Research Council (MR/R008698/1 to LEM, MR/L006588/1 to JF, and MRM008614/2 to DP). AJI is supported by a National Institute for Health Research (NIHR) Clinical Lectureship and acknowledges support from the NIHR and Imperial BRC. CG was funded by a FPU15/03698 PhD fellowship from the Spanish Ministry of Education, Culture and Sport. We thank the CHERUB cooperative and IciStem consortium for support and continuous discussion of results; staff members at University College London Hospitals NHS Trust, Imperial College Healthcare NHS Trust, and Mortimer Market Centre; Nina Parmahand, Rebecca Matthews, Laura Waters, Helen Brown, Águeda Hernández Rodríguez, Victoria González Soler, and Belén Rivaya Sánchez (Microbiology Department of the Hospital Germans Trias i Pujol, Barcelona, Spain), and Dorien de Jong and Ninée Buchholtz (Translational Virology Group of the Department of Medical Microbiology of the UMC Utrecht, Utrecht, Netherlands).
Funding Information:
This study was funded by a Wellcome Trust Senior Fellowship in Clinical Science to RKG (WT108082AIA) and amfAR (American Foundation for AIDS Research), through the amfAR Research Consortium on HIV Eradication (ARCHE) programme (AmfAR 109858-64-RSRL). We also acknowledge funding from Oxford and Cambridge Biomedical Research Centres (BRCs) and the Medical Research Council (MR/R008698/1 to LEM, MR/L006588/1 to JF, and MRM008614/2 to DP). AJI is supported by a National Institute for Health Research (NIHR) Clinical Lectureship and acknowledges support from the NIHR and Imperial BRC. CG was funded by a FPU15/03698 PhD fellowship from the Spanish Ministry of Education, Culture and Sport. We thank the CHERUB cooperative and IciStem consortium for support and continuous discussion of results; staff members at University College London Hospitals NHS Trust, Imperial College Healthcare NHS Trust, and Mortimer Market Centre; Nina Parmahand, Rebecca Matthews, Laura Waters, Helen Brown, ?gueda Hern?ndez Rodr?guez, Victoria Gonz?lez Soler, and Bel?n Rivaya S?nchez (Microbiology Department of the Hospital Germans Trias i Pujol, Barcelona, Spain), and Dorien de Jong and Nin?e Buchholtz (Translational Virology Group of the Department of Medical Microbiology of the UMC Utrecht, Utrecht, Netherlands).
Publisher Copyright:
© 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
PY - 2020/5
Y1 - 2020/5
N2 - Background: The London patient (participant 36 in the IciStem cohort) underwent allogeneic stem-cell transplantation with cells that did not express CCR5 (CCR5Δ32/Δ32); remission was reported at 18 months after analytical treatment interruption (ATI). Here, we present longer term data for this patient (up to 30 months after ATI), including sampling from diverse HIV-1 reservoir sites. Methods: We used ultrasensitive viral load assays of plasma, semen, and cerebrospinal fluid (CSF) samples to detect HIV-1 RNA. In gut biopsy samples and lymph-node tissue, cell-copy number and total HIV-1 DNA levels were quantified in multiple replicates, using droplet digital PCR (ddPCR) and quantitative real-time PCR. We also analysed the presence of intact proviral DNA using multiplex ddPCR targeting the packaging signal (ψ) and envelope (env). We did intracellular cytokine staining to measure HIV-1-specific T-cell responses. We used low-sensitive and low-avidity antibody assays to measure the humoral response to HIV-1. We predicted the probability of rebound using a mathematical model and inference approach. Findings: HIV-1 viral load in plasma remained undetectable in the London patient up to 30 months (last tested on March 4, 2020), using an assay with a detection limit of 1 copy per mL. The patient's CD4 count was 430 cells per μL (23·5% of total T cells) at 28 months. A very low-level positive signal for HIV-1 DNA was recorded in peripheral CD4 memory cells at 28 months. The viral load in semen was undetectable in both plasma (lower limit of detection [LLD] <12 copies per mL) and cells (LLD 10 copies per 106 cells) at 21 months. CSF was within normal parameters at 25 months, with HIV-1 RNA below the detection limit (LLD 1 copy per mL). HIV-1 DNA by ddPCR was negative in rectum, caecum, and sigmoid colon and terminal ileum tissue samples at 22 months. Lymph-node tissue from axilla was positive for the long-terminal repeat (33 copies per 106 cells) and env (26·1 copies per 106 cells), negative for ψ and integrase, and negative by the intact proviral DNA assay, at 27 months. HIV-1-specific CD4 and CD8 T-cell responses have remained absent at 27 months. Low-avidity Env antibodies have continued to decline. Mathematical modelling suggests that the probability of remission for life (cure) is 98% in the context of 80% donor chimerism in total HIV target cells and greater than 99% probability of remission for life with 90% donor chimerism. Interpretation: The London patient has been in HIV-1 remission for 30 months with no detectable replication-competent virus in blood, CSF, intestinal tissue, or lymphoid tissue. Donor chimerism has been maintained at 99% in peripheral T cells. We propose that these findings represent HIV-1 cure. Funding: Wellcome Trust and amfAR (American Foundation for AIDS Research).
AB - Background: The London patient (participant 36 in the IciStem cohort) underwent allogeneic stem-cell transplantation with cells that did not express CCR5 (CCR5Δ32/Δ32); remission was reported at 18 months after analytical treatment interruption (ATI). Here, we present longer term data for this patient (up to 30 months after ATI), including sampling from diverse HIV-1 reservoir sites. Methods: We used ultrasensitive viral load assays of plasma, semen, and cerebrospinal fluid (CSF) samples to detect HIV-1 RNA. In gut biopsy samples and lymph-node tissue, cell-copy number and total HIV-1 DNA levels were quantified in multiple replicates, using droplet digital PCR (ddPCR) and quantitative real-time PCR. We also analysed the presence of intact proviral DNA using multiplex ddPCR targeting the packaging signal (ψ) and envelope (env). We did intracellular cytokine staining to measure HIV-1-specific T-cell responses. We used low-sensitive and low-avidity antibody assays to measure the humoral response to HIV-1. We predicted the probability of rebound using a mathematical model and inference approach. Findings: HIV-1 viral load in plasma remained undetectable in the London patient up to 30 months (last tested on March 4, 2020), using an assay with a detection limit of 1 copy per mL. The patient's CD4 count was 430 cells per μL (23·5% of total T cells) at 28 months. A very low-level positive signal for HIV-1 DNA was recorded in peripheral CD4 memory cells at 28 months. The viral load in semen was undetectable in both plasma (lower limit of detection [LLD] <12 copies per mL) and cells (LLD 10 copies per 106 cells) at 21 months. CSF was within normal parameters at 25 months, with HIV-1 RNA below the detection limit (LLD 1 copy per mL). HIV-1 DNA by ddPCR was negative in rectum, caecum, and sigmoid colon and terminal ileum tissue samples at 22 months. Lymph-node tissue from axilla was positive for the long-terminal repeat (33 copies per 106 cells) and env (26·1 copies per 106 cells), negative for ψ and integrase, and negative by the intact proviral DNA assay, at 27 months. HIV-1-specific CD4 and CD8 T-cell responses have remained absent at 27 months. Low-avidity Env antibodies have continued to decline. Mathematical modelling suggests that the probability of remission for life (cure) is 98% in the context of 80% donor chimerism in total HIV target cells and greater than 99% probability of remission for life with 90% donor chimerism. Interpretation: The London patient has been in HIV-1 remission for 30 months with no detectable replication-competent virus in blood, CSF, intestinal tissue, or lymphoid tissue. Donor chimerism has been maintained at 99% in peripheral T cells. We propose that these findings represent HIV-1 cure. Funding: Wellcome Trust and amfAR (American Foundation for AIDS Research).
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U2 - 10.1016/S2352-3018(20)30069-2
DO - 10.1016/S2352-3018(20)30069-2
M3 - Article
C2 - 32169158
AN - SCOPUS:85084215267
SN - 2352-3018
VL - 7
SP - e340-e347
JO - The Lancet HIV
JF - The Lancet HIV
IS - 5
ER -