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Published in final edited form as: Lancet HIV. 2024 Jun;11(6):e389–e405. doi: 10.1016/S2352-3018(24)00090-0

Dynamics of virological and immunological markers of HIV persistence after allogeneic hematopoietic stem cell transplantation in the IciStem Cohort: a prospective observational cohort analysis

Maria Salgado 1,2,3,*, Cristina Gálvez 1,*, Monique Nijhuis 4,5, Mi Kwon 6,7, E Fabian Cardozo-Ojeda 8,9,$, Jon Badiola 10, Matthew J Gorman 11,12,$, Laura EP Huyveneers 4, Victor Urrea 1, Alessandra Bandera 13,14, Björn-Erik Ole Jensen 15, Linos Vandekerckhove 16, Manuel Jurado 9, Kavita Raj 17, Julian Schulze zur Wiesch 18,19, Rebeca Bailén Almorox 6, Johanna M Eberhard 18,19,20,$, Mitja Nabergoj 21,22,$, Gero Hutter 23, Raquel Saldaña-Moreno 24, Sharon Oldford 25, Lisa Barrett 25, Maria Luisa Montes Ramirez 3,26, Salisu Garba 8,27,$, Ravi Kumar Gupta 28, Boris Revollo 29, Christelle Ferra-Coll 30,31, Jurgen Kuball 32, Galit Alter 11,12,$, Asier Sáez-Cirión 33, Jose Luis Diez-Martin 6, Elizabeth R Duke 8,34, Joshua T Schiffer 8,34,35, Annemarie Wensing 4,36, Javier Martinez-Picado 1,2,3,31,37; IciStem Consortium£
PMCID: PMC11417461  NIHMSID: NIHMS2001014  PMID: 38816141

Abstract

Background

Allogeneic haematopoietic stem-cell transplantation (allo-HSCT) markedly reduces HIV reservoirs, but the mechanisms by which this occurs are only partly understood. In this study, we aimed to describe the dynamics of virological and immunological markers of HIV persistence after allo-HSCT.

Methods

In this prospective observational cohort study, we analysed the viral reservoir and serological dynamics in IciStem cohort participants with HIV who had undergone allo-HSCT and were receiving antiretroviral therapy, ten of whom had received cells from donors with the CCR5Δ32 mutation. Participants from Belgium, Canada, Germany, Italy, the Netherlands, Spain, Switzerland, and the UK were included in the cohort both prospectively and retrospectively between June 1, 2014 and April 30, 2019. In the first 6 months after allo-HSCT, participants had monthly assessments, with annual assessments thereafter, with the protocol tailored to accommodate for the individual health status of each participant. HIV reservoirs were measured in blood and tissues and HIV-specific antibodies were measured in plasma. We used the Wilcoxon signed-rank test to compare data collected before and after allo-HSCT in participants for whom longitudinal data were available. When the paired test was not possible, we used the Mann-Whitney U test. We developed a mathematical model to study the factors influencing HIV reservoir reduction in people with HIV after allo-HSCT.

Findings

We included 30 people with HIV with haematological malignancies who received a transplant between Sept 1, 2009 and April 30, 2019 and were enrolled within the IciStem cohort and included in this analysis. HIV reservoirs in peripheral blood were reduced immediately after full donor chimerism was achieved, generally accompanied by undetectable HIV-DNA in bone marrow, ileum, lymph nodes, and cerebrospinal fluid, regardless of donor CCR5 genotype. HIV-specific antibody levels and functionality values declined more slowly than direct HIV reservoir values, decaying significantly only months after full donor chimerism. Mathematical modelling suggests that allogeneic immunity mediated by donor cells is the main viral reservoir depletion mechanism after massive reservoir reduction during conditioning chemotherapy before allo-HSCT (half-life of latently infected replication competent cells decreased from 44 months to 1,5 months).

Interpretation

Our work provides, for the first time, data on the effects of allo-HSCT in the context of HIV infection. Additionally, we raise the question of which marker can serve as the last reporter of the residual viraemia, postulating that the absence of T-cell immune responses might be a more reliable marker than antibody decline after allo-HSCT.

Funding

This study was supported by amfAR (ARCHE), NIH/NIAID and by Dutch Aidsfonds.

INTRODUCTION

HIV-1 infection has been largely controlled through the use of antiretroviral therapy (ART). However, ART alone is incapable of clearing the virus from cellular reservoirs, and rapid viral rebound is usually observed after ART interruption1. A major effort is underway to develop an effective curative strategy to allow people with HIV (PWH) to safely discontinue ART, and so avoid stigma and potential long-term ART-associated toxicity.

Important efforts have been made to try to cure HIV infection through viral latency modulating therapies, cellular or humoral immunotherapies, and gene therapies. To date, only allogeneic hematopoietic stem cell transplantation (allo-HSCT) has managed to shrink the viral reservoir and even achieve 6 putative cases of cure or long-term remission in the absence of ART (Berlin2, London (IciS-36)3, and Dusseldorf (IciS-19)4, and New York5, City of Hope6, and Geneva (IciS-34)7 respectively), although the precise mechanisms are not yet fully understood. Postulated as a key component in achieving cure are cells with the homozygous CCR5Δ32 mutation, which prevents graft infection with R5-tropic HIV, used in five of the cases8. However, significantly decreased viral reservoirs have also been described in PWH on ART after allogeneic transplantation with CCR5wt/wt donor cells9. We have previously described how other transplantation-associated mechanisms, such as faster time-to-engraftment and graft-versus-host disease (GvHD), correlate with reservoir reduction after transplantation through a graft-versus-HIV reservoir (GvR) effect10, and may critically influence viral rebound probabilities10. A better understanding of these findings may improve future efforts to achieve reservoir reduction or elimination.

Currently, the limited and sporadic number of allo-HSCT performed in PWH prevents definitive conclusions about the dynamics of HIV reservoir persistence, mechanisms that deplete the latent HIV reservoir, and potential biomarkers that identify an HIV control phenotype11. The IciStem consortium (www.icistem.org) has assembled a large and comprehensive observational cohort of PWH, composed of 30 registered and closely monitored transplant recipients with severe hematological malignancies undergoing allo-HSCT. Partial data from the cohort have been previously published as isolated cases or with a more immunological approach3,4,10,12–14. Here, we present new follow up data and integrate multiple parameters with the aim of providing new insights into the mechanisms responsible for HIV reservoir depletion observed after allo-HSCT, here we describe the dynamics of virological and immunological markers of HIV persistence after allo-HSCT.

METHODS

Participants and Study Design

The IciStem cohort currently includes 48 registered participants from 7 European countries and Canada (Appendix Page 10) from 2014 to 2022. We have included in the cohort any PWH willing to be included in the cohort that either had received an allogeneic stem cell transplantation or was scheduled to receive one in the next months. After excluding 18 individuals (8 scheduled for transplants that were cancelled after inclusion mainly due to disease evolution, and 10 transplanted individuals for whom sample collection or follow-up was not possible), 30 followed-up PWH post-allogenic hemopoietic stem cell transplantation (allo-HSCT) with available samples were included in this study and were analyzed both prospectively and retrospectively. The study was approved by the research ethics committees of the participating centers/countries. All participants provided informed consent. Publications involving partial results are listed in Table 13,4,7,10,12–16.

Table 1.

Demographic and virological data clinical data for the IciStem cohort participants. Word abbreviations: 3TC: lamivudine, ABC: abacavir, ART: antiretroviral therapy, ATI: analytical treatment interruption, AZT: zidovudine, BIC: bictegravir, DDI: didanosine, DRV/r: darunavir boosted ritonavir, DTG: dolutegravir, EFV: efavirenz, ENF: enfuvirtide, EVG/c: elvitegravir+cobicistat, FTC: emtricitabine, HSCT: hematopoietic stem cell transplant, MVC: maraviroc, n.a.: non-applicable or unknown, NVP: nevirapine, RAL: raltegravir, RPV: rilpivirine, TAF: tenofovir alafenamide, TDF: tenofovir, TI: Treatment Interruption.

Table 1. Demographic and virological data
IciStem ID Gender Age at HSCT (years) HIV diagnosis (years before HSCT) HIV ART (years before HSCT) HIV ART HIV tropism TI post-transplant (outcome) References
1 Male 32 −1 −1 ABC, 3TC, RAL R5 TI 2017 (rebound) 10,13,15
2 Male 31 0 0 ABC, 3TC, RAL R5 No 13, 15
3 Male 50 −17 −17 Pre-HSCT: 1st AZT, 2nd AZT+DDI, 3rd +IP. At HSCT: EFV, 3TC, TDF R5/X4 No 10,13,15
4 Male 35 −4 −4 TDF, FTC, NVP. At HSCT: ABC, 3TC, RAL R5 No 13,16
5 Male 53 −14 −14 TDF/FTC, RAL, MVC, ENF R5 No 12,13
6 Male 40 −2 −2 EFV, 3TC, TDF R5/X4 No 10,13
7 Female 42 0 0 TDF, FTC, RAL n.a. No
8 Male 57 −5 0 ABC, 3TC, DTG R5 No 13
9 Male 54 −5 −5 TDF, FTC, EVG/c n.a. No
10 Male 54 n.a. n.a. n.a. n.a. No
11 Male 60 −19 −19 TDF, FTC, DTG R5 No 12,13
12 Male 32 −2 −2 Pre-HSCT: EFV, FTC, TDF. At HSCT: ABC, 3TC, EFV R5/X4 No 13
17 Male 46 −16 −13 TDF, FTC + DRV/r +RAL n.a. No 10,13
19 Male 43 −5 −3 Pre-HSCT: TDF, FTC, DRV/r. At HSCT: TDF, FTC, RAL R5 (X4=0.14%) ATI 2018 (no rebound) 4,13
20 Male 56 −9 n.a. n.a. X4 No 13
21 Male 58 −20 n.a. ABC, 3TC, DTG R5 No
23 Male 59 −24 −23 TAF, FTC, BIC R5/X4 No 13
27 Male 48 −8 −8 ABC, 3TC, DDI n.a. No 10,13
28 Male 46 −11 −11 ABC, 3TC, RAL n.a. TI 2019 (rebound) 10,13
29 Male 47 −6 −6 ABC, 3TC, DTG X4 No 13
31 Male 55 −12 −6 Pre-HSCT: TDF, FTC, EFV. At HSCT: ABC, 3TC, RAL X4 No
32 Male 51 −2 −2 TDF, FTC, RPV n.a. No
33 Female 62 −2 0 TDF, FTC, RAL n.a. No
34 Male 46 −28 −17 FTC, TAF, DTG n.a. ATI 2021 (no rebound) 7
35 Male 46 −4 n.a. n.a. n.a. No
36 Male 37 −13 −4 3TC, TDF, EFV R5 ATI 2017 (no rebound) 2,14
37 Male 58 −12 0 3TC, TDF, EFV n.a. No
43 Male 29 −1 −1 At HSCT: TDF, FTC, MVC; ABC, 3TC, RAL n.a. No
45 Male 43 −3 −3 Pre-HSCT: FTC+TAF+EVG/c. At HSCT: FTC, TAF, RAL n.a. No
48 Male 36 −1 −1 ABC, 3TC, DTG R5 No
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Procedures

Clinical data was collected by each site during the follow-up. Gender data was self-reported. The specifics of the clinical follow-up of each participant are detailed in Table 1 and 2. All the laboratory procedures were centralized by technique to a single i site to avoid variations among procedures at different sites. HIV reservoirs in blood and tissues were measured using ddPCR, ultrasensitive viral load and quantitative viral outgrowth assay as detailed in the Appendix (Pages 10–16). HIV antibody quantification and functionalities were calculated as described in the extended methods (Appendix Pages 10–14) by using New Lav Blot I (BIO-RAD) kit, VITROS Anti- HIV-1 assay, Lag-avidity and the customized multiplex Luminex assay for system serology.

Table 2.

Hematological diseases and transplant-associated clinical data for the IciStem cohort participants. Word abbreviations: AML: acute myeloid leukemia, ATG: anti-thymocyte globulin, BK+: bacilloscopically positive, BM: Bone marrow, BSI: bloodstream infection, BU: busulfan, CLO: clofarabine, CML: chronic myeloid leukemia, CMV-R: cytomegalovirus reactivation, CsA: cyclosporine A, CY: cyclophosphamide, DDI: didanosine, DLBCL: diffuse large B-cell lymphoma, EBV-R: Epstein-Barr virus reactivation, FDC: full donor chimerism, FLU: fludarabine, GC: glucocorticosteroids, GvHD: graft vs host disease, Haplo: mismatched family donor, Haplo-cord: single cord blood supported by haplo CD34+ cells, HHV8-R: human herpes virus 8 reactivation, HL: Hodgkin lymphoma, HLH: hemophagocytic lymphohistiocytosis, HSCT: hematopoietic stem cell transplant, HSV-R: herpes simplex virus reactivation, LACE: lomustine, cyclophosphamide, cytosine arabinoside, and etoposide, MAC: myeloablative conditioning, MDS: myelodysplastic syndrome, MEL: melphalan, MF: myelofibrosis, MMF: mycophenolate mofetil, MMUD: mismatched unrelated donor 9/10, MRSA: methicillin-resistant Staphylococcus aureus, MS: myeloid sarcoma, MSD: matched sibling donor, MTX: methotrexate, MUD: matched unrelated donor 10/10, n.a.: non-applicable or unknown, NLH: non-Hodgkin lymphoma, PB: peripheral blood, PBL: plasmablastic lymphoma, PT-CY: post-transplant cyclophosphamide, RIC: reduced-intensity conditioning, TAC: tacrolimus, TBI: total body irradiation, TT: thiotepa, wt: wild-type.

Table 2. Hematological diseases and transplant-associated data
IciStem ID Hematological disease HSCT type CCR5 donor Conditioning regimen GvHD prophylaxis Last follow-up status Decease (months after HSCT) Engraftment Time to FDC PB (months) Time to FDC T cells (months) Time to FDC BM (months) GvHD Grade/severity HSCT-associated infections
1 Burkitt’s NHL Haplo-cord WT/WT MAC: ATG, FLU, BU, CY CsA, GC Alive Yes 18 n.a. 12 No BK virus
2 HLH MSD Δ32/WT RIC: ATG, FLU, MEL CsA, MTX Dead 28.6 Yes 1 1 3.5 Chronic Severe CMV-R, Kaposi, Pseudomonas (urinary tract), C. difficile, MRSA BSI
3 NK-NHL MSD WT/WT RIC: FLU, MEL CsA, MTX Alive Yes 1 1 1 Acute Grade I No
4 DLBCL Haplo-cord Δ32/Δ32 RIC: ATG, FLU, BU, CY CsA, GC Dead 2.6 Yes n.a. 2.4 No CMV-R
5 MDS Haplo-cord Δ32/Δ32 ATG, FLU, BU CsA, MMF, GC Dead 2.3 Yes 1,2 n.a. n.a. Acute Grade I Sepsis, fungal infection, EBV-R
6 HL Haplo WT/WT RIC: FLU, BU, CY PT-CY, CsA, MMF Alive Yes 3,5 1 6 Acute Grade III CMV-R, C. difficile
7 DLBCL MSD WT/WT MAC: TBI, CY Dead 1.0 Yes n.a. n.a. n.a. No
8 MF Haplo WT/WT RIC: FLU, BU, CY PT-CY, CsA, MMF Dead 1.5 Not reached n.a. n.a. n.a. No Fungal infection
9 MDS MUD WT/WT n.a. Dead 0.4 Not reached n.a. n.a. n.a. No
10 Burkitt’s NHL MSD WT/WT n.a. Dead 0.8 Yes n.a. n.a. n.a. No
11 AML MUD Δ32/Δ32 1: RIC: ATG,FLU, TBI, 2: RIC: FLU, ATG, treosulfan 1&2: MMF, CsA Dead 3.6 Yes, after 2nd HSCT 1 (after 2nd HSCT) n.a. n.a. No CMV-R, bacterial infections
12 PBL Haplo WT/WT RIC: FLU, CY, BU PT-CY, CsA, MMF Dead 1.8 Yes 1 1.5 n.a. Acute Grade II-III CMV-R, Adenovirus colitis, C. esophagitis, BK+hemorrhagic cystitis
17 DLBCL Haplo WT/WT RIC: FLU, TT, CY CsA, MTX Alive Yes 1 n.a. n.a. No EBV-R
19 AML MUD Δ32/Δ32 RIC: FLU, treosulfan, ATG CsA, MMF/TAC, GC Alive Yes n.a. n.a. 7 Chronic Mild HSV-2-R, HHV8-R, EBV-R, CMV-R
20 AML MUD Δ32/Δ32 FLU, BU, alemtuzumab CsA Dead 41.3 Yes 13 10 16 No CMV-R, EBV-R
21 CML MUD Δ32/Δ32 MAC: TBI, CY, ATG CsA, MTX Dead 21.6 Yes 3,3 n.a. n.a. Yes, n.a. C. difficile, oral HSV, CMV-R
23 AML Haplo WT/WT BU, cytarabine, idarubicin MMF, TAC Alive Yes 6 6 6 No Neutropenic fever, CMV-R
27 NHL MSD WT/WT RIC: FLU, CY CsA, MTX Alive Yes n.a. 5.3 n.a. Chronic Mild No
28 HL MUD WT/WT RIC: FLU, MEL TAC, sirolimus Alive Yes n.a. 1 n.a. Acute/Chronic Grade II/Moderate CMV-R
29 AML MUD WT/WT MAC: FLU, BU PT-CY, CsA, MMF Dead 4.3 Yes 1 1 1 Acute Grade III/IV No
31 AML MUD WT/WT MAC: FLU, BU PT-CY, TAC, MMF Alive Yes 1 1 1 Acute Grade III/IV CMV-R, E. coli BSI
32 AML MUD WT/WT BU, CY PT-CY Alive Yes 5.5 Chronic n.a. n.a
33 AML MUD Δ32/Δ32 FLU, BU CsA Alive Yes 4 n.a. 4 Acute Grade II-III CMV-R
34 MS MMUD WT/WT MAC: TBI, CY, FLU, CLO PT-CY, TAC, MMF Alive Yes 1 1 1 Acute/Chronic Grade I/mild CMV-R
35 PBL MSD WT/WT n.a n.a Dead 9.6 Yes 1 1 1 Acute Grade II EBV-R, pneumonia
36 HL MMUD Δ32/Δ32 RIC: LACE CsA, MTX Alive Yes 1 n.a. n.a. Acute Grade I CMV-R, EBV-R
37 MF MMUD Δ32/Δ32 FLU, BU CsA Dead 3.2 Yes 3 n.a. n.a. Acute Grade II-IV Peritonitis
43 DLBCL MSD WT/WT RIC: FLU, MEL CyA+Mtx Alive Yes NA NA NA Chronic Severe P.jirovecii
45 HL MSD WT/WT RIC: FLU, MEL CsA, MTX Alive Yes 18 n.a. n.a. Acute Grade II S.epidermidis and pulmonary aspergillosis
48 PBL 1:MMUD
2:Haplo		 1: Δ32/Δ32
2: WT/WT		 1: RIC: FLU, BU, CY
2: RIC: ATG, FLU, TT		 PT-CY, TAC, MMF Alive Yes 1: Not reached (2nd HSCT) 2: 1 1: Not reached (2nd HSCT) 2: 1 1: Not reached (2nd HSCT) 2: 1 No S.epidermidis BSI
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Statistical analysis

The main outcome of the study was to determine the primary factors related to transplantation that are related with the HIV reservoir elimination. The Wilcoxon signed-rank test was performed to compare data before and after allo-HSCT in the cases where longitudinal data were available. When paired tests were not possible, an unpaired test was performed (a Mann-Whitney U test). A mathematical model was developed to study the drivers of HIV reservoir reduction in PWH after allo-HSCT. Extensive statistical analysis and mathematical modeling are also detailed in the extended methods (Appendix Pages 10–14).

Role of the funding source

The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

RESULTS

Between Sept 1, 2009 and April 30, 2019, 30 people with HIV and haematological malignancies received a transplant (tables 1, 2). All participants were White and cisgender, with two exceptions (IciS-7 was transgender and IciS-36 is mixed race). Ten individuals received donor cells with the CCR5Δ32 mutation (nine homozygous and one heterozygous), and the remainder received cells from donors with homozygous wild-type CCR5. Eight participants had acute myeloid leukaemia, four had Hodgkin lymphoma, four had diffuse large B-cell lymphoma, two had Burkitt’s lymphoma, two had myelodysplastic syndrome, three had plasmablastic lymphoma, one had chronic myeloid leukaemia, one had haemophagocytic lymphohistiocytosis, two had myelofibrosis, one had myeloid sarcoma, one had natural killer-non-Hodgkin lymphoma, and one had other nonHodgkin lymphomas. For 14 patients, the graft source was an unrelated donor and in 13 patients the graft source was from a related donor, including five from a haploidentical sibling. Three patients received single umbilical cord blood cells combined with cells from mismatched donors (haplo-cord). Three participants (IciS-4, IciS-11, and IciS-48) received two transplants due to graft failure. 14 (47%) of 30 individuals died after alloHSCT due to the procedure or underlying disease (ten [71%] patients within the first 4 months). Among the 22 prospective cases, 12 (55%) patients were alive at 6 months and 11 (50%) at 12 months. Follow-up was extended up to 8 years. All participants remained on ART during the transplant procedure, with the exception of IciS-06 whose treatment was discontinued between day 5 and day 24 after allo-HSCT due to severe mucositis, with no plasma evidence of HIV-RNA during this interval.

Comprehensive HIV reservoir measurements were performed before and after allo-HSCT on more than 100 blood samples from the participants at different time points (Appendix Pages 2–3). Detectable in most baseline samples were total HIV-DNA (22/22) and ultra-sensitive viral load (usVL) (12/16) values that predominantly became undetectable post-transplantation (Fig. 1A, 1B, 1D, 1E, Appendix Pages 2–4). Moreover, a striking reduction in HIV-DNA and usVL was observed at the first timepoint after full donor chimerism when compared to related samples before allo-HSCT (Fig 1A & 1C, Appendix Pages 2–3) (n=13; Appendix Pages 4). Except for IciS-01, no replication-competent virus could be detected in any of the samples tested by the quantitative viral growth assay (qVOA) >12 months of allo-HSCT (Fig. 1G). In contrast, replication-competent virus was detected in 11 of the 13 samples obtained before allo-HSCT. Infectious units per million cells fell to undetectable levels after full donor chimerism in the 3 participants analyzed with longitudinal samples both before allo-HSCT and after full donor chimerism (Appendix Page 5). Noteworthy, declines in HIV-DNA, residual viremia, and replication-competent viruses were similar for individuals transplanted with CCR5Δ32 and CCR5wt donor cells (Appendix Pages 2–3 and 5).

Figure 1. HIV reservoir in blood and tissues.

Figure 1.

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(A) Pairwise comparison of HIV-DNA for participants with samples from before allo-HSCT and after reaching FDC. (B) Proviral HIV-DNA in longitudinal samples; the grey vertical line represents the allo-HSCT date. (C) Decay ratios of HIV-DNA before allo-HSCT and after reaching FDC by donor cell type (CCR5Δ32/Δ32 and CCR5wt/ wt). (D) usVL pairwise comparison for participants with plasma samples before allo-HSCT and after reaching FDC. (E) usVL in longitudinal plasma samples; the grey vertical line represents the allo-HSCT date. (F) Decay ratios of HIV-RNA before allo-HSCT and after reaching FDC by donor cell type (CCR5Δ32/Δ32 and CCR5wt/wt). (G) Non-paired comparison for the replication-competent viruses in a qVOA measured in CD4+ T cells before allo-HSCT and after reaching FDC. (H) Non-paired comparison for proviral HIV-DNA measured in CD4+ T cells isolated from bone marrow. (I) Non-paired comparison for proviral HIV-DNA measured in CD45+ T cells isolated from ileum biopsies. (J) Proviral HIV-DNA measured in CD4+ T follicular helper cells isolated from lymph nodes by fine needle biopsy. (K) Non-paired comparison for ultrasensitive HIV-RNA measured in cerebrospinal fluid. Where more than one sample per participant was tested in tissues after allo-HSCT, the sample with the highest number of cells analysed is shown. For the tissue determinations and qVOA analysis, unpaired tests were used for the comparison because sufficient pairwise determinations of the same participants before and after allo-HSCT were unavailable. Non-filled symbols correspond to undetectable determinations for which the upper limit of detection was assigned on the basis of sample input. Allo-HSCT=allogeneic haematopoietic stem-cell transplantation. FDC=full donor chimerism. usVL= ultrasensitive viral load. qVOA=quantitative viral outgrowth assay. wt=wild-type.

Whenever possible, cerebrospinal fluid (CSF), bone marrow (BM), ileum, and lymph node (LN) biopsies were collected for thorough evaluation of viral reservoirs (sampling detailed at Appendix Page 4). After allo-HSCT, tissues were further analyzed for participants with undetectable blood reservoirs (Fig. 1H–K). The analyses were performed on purified cell populations targets of HIV (CD4+, CD45+, and T follicular helper (TFH) cells in BM, ileum, and LN biopsies, respectively) to increase the likelihood of viral detection. Although HIV reservoirs were detectable in all BM, ileum, and LN biopsies from participants tested before allo-HSCT (n=4, 6, and 1, respectively; Fig. 1H–K, Appendix Page 4), no virus was detected in any samples obtained >12 months after allo-HSCT. Viral RNA was only detectable in 1 pre-transplant CSF sample (out of 7) and in none of the 6 samples analyzed after allo-HSCT (Fig 1K). These results would indicate that HIV reservoir reduction after allo-HSCT is indicative of latent viral reservoir loss in all the tested lymphoid tissues.

We assessed whether the strong viral reservoir decay after allo-HSCT exerted an effect on HIV-specific humoral responses through the impact on decreased antigen stimulation. Although the standard VITROS enzyme immunoassay persistently detected HIV-specific antibodies in most participants years after allo-HSCT (figure 2A, B), the LAg avidity (figure 2D–E) and VITROS avidity assay (figure 2G, H) indicated a progressive reduction in HIV-specific antibody avidity levels after transplantation. A clear reduction was observed when comparing HIV-specific antibody avidity levels before allo-HSCT and at the last collection timepoint after full donor chimerism (n=9; figure 2D–G; appendix p 4), suggesting that the decay dynamics of HIV-specific antibodies was slower than of infected cells. No differences were observed in HIV-specific plasma immunoglobulin decay or avidity between individuals transplanted with CCR5Δ32/Δ32 or CCR5wt/wt donor cells (figure 2C, F, I; appendix p 5). western blot showed that the first antibodies to become undetectable were generally those targeting p18, p24, p40, and p31 (appendix p 6). In four cases, negative patterns were observed in western blots (IciS-19, at month 77 after transplant with CCR5Δ32/Δ32; IciS-23, at month 24 after transplant with CCR5wt/wt; IciS-28, at month 88 after transplant with CCR5wt/wt; and IciS-43, at month 93 after transplant with CCR5wt/wt), corresponding mostly to individuals with antibody avidity levels below the limiting antigen immunoassay threshold of 1,5. Of note was the reduction in HIV-specific IgG antibodies against gp120, while IgG levels against two influenza strains (H1N1 and H3N2), cytomegalovirus, and Epstein-Barr virus remained stable after allo-HSCT (appendix p 7).

Figure 2. HIV-specific antibody levels and avidity.

Figure 2.

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The grey vertical line represents the allo-HSCT date. (A) Pairwise comparison of the standard VITROS EIA for participants with samples from before allo-HSCT and the last sample after reaching FDC. (B) Longitudinal standard VITROS EIA levels. (C) Decay ratios of standard VITROS EIA before allo-HSCT and the last sample after reaching FDC by donor status. (D) Pairwise comparison using the LAg avidity technique for participants with samples from before allo-HSCT and the last sample after reaching FDC. (E) Longitudinal levels of LAg avidity. (F) Decay ratios of LAg avidity before allo-HSCT and the last sample after reaching FDC by donor status. (G) Pairwise comparison for VITROS antibody avidity for participants with samples from before allo-HSCT and the last sample after reaching FDC. (H) Longitudinal levels of antibody avidity according to the VITROS avidity competition assay. (I) Decay ratios of VITROS antibody avidity before allo-HSCT and the last sample after reaching FDC by donor status. Each symbol corresponds to an IciStem participant; open symbols represent levels under the so-called primary infection threshold17 to interpret antibody reduction. EIA=enzyme immunoassay. S/CO=signal to cutoff ratio. Allo-HSCT=allogeneic haematopoietic stem-cell transplantation. FDC=full donor chimerism. LAg=limiting antigen.

We conducted antibody type and functionality studies in 15 participants with available samples ( Appendix Page 4), evaluating 4 functionalities associated with HIV-specific IgG antibodies against gp120 (Fig.3): antibody-dependent neutrophil phagocytosis (ADNP); antibody-dependent cellular phagocytosis (ADCP) of monocytes; antibody-dependent complement deposition (ADCD); and antibody-dependent NK cell activation (ADNKa). Comparing values before allo-HSCT and for the last sample after full donor chimerism, all functionalities tended toward reduction, although statistical significance was only reached for ADCP, which showed the highest levels and highest variance when analyzed in longitudinal samples for most participants (Appendix Page 8).

Figure 3. HIV-specific antibody functionalities.

Figure 3.

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Analyses performed in the 12 IciStem participants indicated in the legend, based on sample availability. A) Antibody-dependent neutrophil phagocytosis (ADNP) follow-up and paired comparison for participants with samples from before allogeneic stem cell transplantation (allo-HSCT) and the last sample after reaching full donor chimera (FDC). B) Monocyte antibody-dependent cellular phagocytosis (ADCP) and paired comparison for participants with samples from before allo-HSCT and the last sample after reaching FDC. C) Induced complement component C3b deposition on gp120-coated target cells (ADCD) follow-up and paired comparison for participants with samples from before allo-HSCT and the last sample after reaching FDC. D) Antibody-dependent cellular cytotoxicity measured by NK cell activation (ADNKa) using CD107a levels and paired comparison for participants with samples from before allo-HSCT and the last sample after reaching FDC. E) Antibody-dependent cellular cytotoxicity measured by NK cell activation (ADNKa) using IFN-γ levels and paired comparison for participants with samples from before allo-HSCT and the last sample after reaching FDC. F) Antibody-dependent cellular cytotoxicity measured by NK cell activation (ADNKa) using MIP-1β levels and paired comparison for participants with samples from before allo-HSCT and the last sample after reaching FDC. The dotted vertical line represents the allo-HSCT date.

We have previously reported long-term remission in HIV-1 infection after analytical 3,4treatment interruption (ATI) in 2 IciStem participants after allo-HSCT with CCR5∆32/∆32 donor cells (IciS-36 and IciS-19, the London and Düsseldorf patients, respectively3,4). Two other participants, IciS-01 and IciS-28, spontaneously discontinued ART 4- and 9-years after allo-HSCT, respectively. Both were transplanted with cells from CCR5wt/wt donors10, but otherwise had distinct immunological and virological profiles while on ART.

IciS-01 was among the few participants still showing detectable proviral HIV-DNA, replication-competent viruses, and residual viremia even 45 months after allo-HSCT (Fig. 1 and Appendix Pages 2–3 and 9). WB was only lacking the p18 band (Appendix Page 6), and antibody levels and avidity were comparable to those of other participants in the first few years after allo-HSCT (Fig. 2). HIV-specific CD8+ T lymphocyte levels were previously reported to be very low at month 4513, and also at month 45, an in-depth analysis of ultrasensitive chimerism revealed a small proportion of recipient cells in blood10.

In contrast, IciS-28 was characterized by an undetectable HIV reservoir in all blood and tissue assays at month +88 after allo-HSCT (Fig. 1 and Appendix Pages 2–3). The HIV-specific antibody level was minimal even in standard determinations and accompanied by a lack of antibody functionality and negative WB (Fig. 2 and Appendix Page 6) indistinguishable from those uninfected. We previously reported a small presence of HIV-specific CD8+ T-cells for IciS-28, but higher than for IciS-0113.

In both IciS-01 and IciS-28, high-level viremia was observed 1 and 3 months after ART interruption, respectively, although the precise time of viral rebound is unknown. ART was promptly resumed, and no acute retroviral syndrome was detected in either participant. In IciS-28, all HIV-specific WB bands reappeared after plasma viremia was detected (month 113, Appendix Page 6). Proviral HIV-DNA and replication-competent viruses were detectable in both cases 6 months after ART resumption, by which time low-level plasma viremia was also detected (Appendix Page 9).

To assess conditioning and GvR impact on the HIV reservoir in individuals receiving allo-HSCT, we adapted previously developed mathematical models to study HIV cure18,19. We used a nonlinear mixed-effects approach to explore 2 mechanistic assumptions regarding allo-HSCT impact on reservoir reduction: i) infected cells are depleted by conditioning only, or ii) by conditioning and a GvR effect measured in direct proportion to donor T-cell chimerism levels (Fig. 4A). The model includes total CD4+ T-cells, latently infected cells with replication-competent HIV-DNA, productively activated infected cells, and non-productively infected cells with defective HIV-DNA. Since all participants were on ART, new productively infected cells only originated after latent cell reactivation with replication-competent HIV-DNA (Fig. 4A).

Figure 4. Mathematical modeling of HIV reservoir dynamics after allo-HSCT.

Figure 4.

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A) Schematics of the mathematical model, with variables as follows: latently infected cells with replication-competent HIV-DNA (LP), productively infected cells (IP), non-productively infected cells with defective HIV-DNA (LD), total CD4+ T-cells (T4), virus (V), and a surrogate for HIV-specific antibody concentration (A). In the model t = 0 is the transplantation date and the conditioning period is t ∈ [−10,0) days. Parameters: κC, cell depletion rate due to conditioning; αT: CD4+ T-cell maximum proliferation rate; K, carrying capacity of cell proliferation; δL, death rate of latent cells; ξ reactivation rate of latent cells; αA: antibody proliferation rate; δA, antibody loss rate; δP, death rate of productively infected cells; π, virus production rate; γ, virus clearance rate; κGVH, rate of cell depletion relative to chimerism (Ct). AICc: corrected Akaike information criterion. During fitting we found κGVH > 0 to be the most parsimonious model (ΔAICc=AICcH0 - AICcH1=51 and p<0.0001 using the loglikelihood ratio test). Β) T-cell chimerism observations (medians in bold/black). Best model predictions (C-H): C) blood CD4+ T-cell count; D) HIV-DNA per CD4+ T-cells; E) plasma ultra-sensitive HIVRNA-viral load; F) infected units per million cells per the qVOA assay; G) low sensitivity anti-HIV antibody (diluted ELISA observations); and H) model predictions of the HIV-DNA/mL. Black/bold solid line: model predictions using median parameter estimates (see table 1 in Appendix Page 17). Gray region: 10th and 90th quantiles from 1,000 simulations by the best model randomly selecting values from the population distributions of the estimated parameters (see table 1 in Appendix Page 17). Filled circles: observations over the limit of detection. Open circles: observations below the limit of detection. Red dashed line: model simulation assuming κGVH = 0. I) Contribution of different components to the total reservoir turnover rate and estimated reservoir half-life at different timepoints before and after transplantation as observed for total HIV-DNA and by qVOA. Blue: reservoir half-life equivalent to cell-loss preconditioning using historical values20,21. Purple: reservoir half-life equivalent to depletion due to conditioning. Green: cell proliferation. Red: reservoir half-life equivalent to depletion proportional to levels of chimerism. Mpt: months post-transplantation.

Using interpolated T-cell chimerism levels from 22 IciStem participants, we fit the model to longitudinal CD4+ T-cell concentrations, several assayed viral reservoir quantifications (HIV-DNA, HIV-RNA, quantitative viral outgrowth (qVOA)), and anti-HIV antibody levels (LS-ELISA) in blood (Fig. 4A–G). Using model selection theory (see Extended Methods), we found that a model with both conditioning and HIV-infected cell depletion proportional to the observed T-cell chimerism best explained the observed timing and magnitude of the reduction (ΔAICc=51 and p<0.0001 log likelihood ratio test. See Fig 4A and Appendix Page 17).

Our model predicts that T-cell proliferation allows HIV reservoir levels to recover in response to extremely rapid reservoir depletion during conditioning (Fig 4H–I). Thus, only donor-cell GvR could explain post-transplant reservoir reduction and the reduced half-life of latently-infected replication-competent cells from 44 to 1.5 months (95%CI: 24 days—5 months) in the 6 months after transplant. This would suggest that the GvR effect may indeed be the main driver of reservoir shrinkage after allo-HSCT. The model also predicts that antibody reduction is slower than reservoir decay (Fig. 4G).

DISCUSSION

A comprehensive overview of the variable reservoir effects of allo-HSCT is provided by long-term follow-up of the IciStem cohort, the largest reported so far, with 30 PWH who have undergone allo-HSCT. In this cohort, acute myeloid leukemia, Hodgkin lymphomas, and diffuse large B-cell lymphomas were the most prevalent underlying hematological diseases that led to allo-HSCT, in agreement with previous clinical series20–22. Transplant-associated survival was similar to rates reported in European studies in other PWH16. Those results indicate that allo-HSCT safety and feasibility for PWH meeting transplant criteria and using diverse types of donors are similar to those reported for the population without HIV15,20,21.

Reduced HIV reservoirs after allo-HSCT have previously been reported in different case reports2,3,9,10,16,22–24 and macaque studies25. Comprehensive longitudinal follow-up of our large cohort has allowed us not only to generalize those previous observations, but also to corroborate HIV reservoir clearance dynamics over many months.

Our observation of a dramatically reduced HIV reservoir after full donor chimerism had been achieved is supported by previous case reports that link the persistence of positive proviral HIV-DNA to mixed chimerism10,20. This would suggest a window of vulnerability for de novo infection of donor cells prior to full chimerism, further underlined by strong CD4+ T-cell activation and exposure to HIV antigens in the post-transplant period in most participants13. For CCR5Δ32-donor cases, immediate and tight post-transplant viral control might be critical to prevent viral replication, especially when previous CXCR4 tropic virus is detected, as happened with the Essen patient26,27.

However, the fact that HIV reservoir reduction after allo-HSCT was no different for individuals who received cells from CCR5Δ32 or CCR5wt donors would point to the intervention rather than the origin of the cells as the reason for reduction. In contrast, the HIV remission cases reported to date suggest that the CCR5Δ32 mutation, which renders cells refractory to HIV R5 strain infections, might be beneficial in achieving HIV cure3–5. It is conceivable that a protective effect against post-transplant viral rebound with CCR5Δ32 donor cells may be achieved after effective reservoir reduction. Therefore, alternative strategies may be needed to mimic this barrier to viral reshedding in people transplanted with CCR5wt donor cells.

Reassuringly, we also observed that undetectable proviral HIV-DNA in peripheral blood was accompanied by undetectable reservoirs in BM, LN, gut-associated lymphoid tissue (GALT), and CSF tissue >12 months after allo-HSCT, even when test sensitivity was maximized by isolating the main HIV-infected target cells in each tissue. In line with our data, a recent study reports that major histocompatibility complex-matched allo-HSCT in 4 SIV-infected ART-suppressed macaques resulted in long-term suppression in 2 animals, suggesting that allogeneic immunity is a major driver of reservoir clearance occurring first in peripheral blood and then in tissues25. While our results show that HIV reservoirs are globally reduced in the body, we cannot rule out the possibility that some replication-competent viruses may hide in tissue sanctuaries, as has been observed in necropsy studies of IciS-05 and IciS-1112 or as evidenced by viral relapse following ART interruption in IciS-28 and other cases28.

Antibody levels and avidity also progressively decreased after allo-HSCT, but more slowly than viral reservoir reduction. Thus, while antibody decay most likely follows progressive viral antigen reduction after allo-HSCT, whether this implies persistence of recipient plasma cells or de novo donor antibody-producing B cells is an open question. HIV-specific antibody functionalities were reduced, but still detectable, after allo-HSCT. The well-known fact that, after allo-HSCT, humoral immunity against various vaccine-preventable diseases is lost over time29 would help understand HIV-specific antibody decay. Nonetheless, we saw no pronounced decline in antibody serology against other viruses such as influenza, CMV or EBV – possibly explained by some level of reactivation or re-exposure to these viral antigens. Further comparison with the donors’ serology levels of these markers would be of interest; however, we did not have access to samples from the donor.

Four of our cases showed complete seroreversion of WB-measured HIV-specific antibodies to under threshold levels in the standard ELISA, comparable to those of a HIV-uninfected person. Only a few cases of complete seroreversion have been documented, mostly related to natural HIV control30,31. Complementary results regarding T-cell immune responses in the IciStem cohort have recently been published13. Those residual humoral or cellular responses in transplanted individuals with undetectable reservoirs may act as an immunological surrogate marker of residual viral exposure that is undetectable with virological tools.

Indeed, this may be the case for participant IciS-28, who discontinued ART in an unplanned and unsupervised manner, rebounding only 3 months later despite having previously undetectable reservoirs in blood, BM, GALT, lymph node and CSF. Low but detectable Gag-, Nef- and Pol-specific T-cell responses were found in peripheral blood after allo-HSCT13 even though no HIV-specific antibodies were detected by WB or system serology by month +88 after allo-HSCT. Although, superinfection could not be formally ruled out in this case, due to the absence of sequences before allo-HSCT, the study of IciS-28 suggests that the absence of detectable viral reservoirs by multiple techniques and in different tissues and the lack of plasma antibody reactivity might not be sufficient to predict HIV remission after ART interruption. Given that Gag-, Nef- and Pol-specific T-cell responses were the only traces of HIV persistence found in IciS-28 before ART interruption, we speculate that persistent T-cell responses may also suggest HIV persistence in profound HIV reservoir depletion, as occurs in PWH undergoing allo-HSCT. Of note, in specific cases T-cell responses follow different decay dynamics before total disappearance. In the Düsseldorf patient (IciS-19), HIV-1-specific CD8+ T-cell decline after allo-HSCT took several years, but only some weeks in the London patient (IciS-36), probably due to delayed donor chimerism and DNA undetectability in the former3,4. Proving this hypothesis would require extended immunological studies in other cases transplanted with CCR5wt/wt donor cells and in long-term ART-free virus remission, such as reported in preliminary data for IciS-347 and in 2 allo-HSCT recipient macaques7. Therefore, an effective biomarker is still needed that enables viral rebound prediction in the unique cases where viral eradication seems possible.

Finally, mathematical modeling allowed us to mechanistically integrate CD4+ T-cell concentrations, viral assay results (HIV-DNA, HIV-RNA, qVOA), anti-HIV antibody levels, and T-cell chimerism data. To reduce model misspecification bias, we explored the reservoir reduction mechanisms around which there is consensus in the immediate post-transplant period: conditioning and GvR. The best model fit supports the hypothesis that the GvR effect after allo-HSCT is the main driver of the viral reservoir shrinkage that becomes apparent after full donor chimerism. Despite data heterogeneity, the model estimates that reservoir half-life decreases from 44 months pre-transplant to 1.5 months following full donor chimerism. This effect, which persists long after the impact of conditioning, appears to be a persistent donor engraftment effect. However, a limitation regarding this estimate is that the 1.5-month half-life applies only to the time frame when HIV reservoir measurements (in this case, qVOA) are above the limit of detection, which was an average of 6 months after allo-HSCT.

Our work has some other limitations. First, no generalized study protocol could be applied due to heterogeneity of participants, clinical centers, hematological diseases, treatments, and sampling. This fact has greatly complicated the logistics of the study. Here, we also include information from isolated cases for which partial information has previously been published, given the maximum interest in the cure forHIV. Although the study design has limitations, we aimed to achieve the larger number of transplants followed up so far with the application of mathematical modeling to our data. Second, pre-transplant samples were not available for retrospective post-transplant entrants to the cohort (8 of 30 PWH). Those 8 PWH, in providing us with important information on HIV elimination mechanisms after allo-HSCT, allow insights into long-term HIV reservoir dynamics and the corresponding immune responses. Furthermore, people surviving years after allo-HSCT with CCR5wt with undetectable reservoirs may be perfect candidates to test future viral remission strategies.

In conclusion, we describe, for the first time, HIV reservoir reduction dynamics for a cohort of 30 PWH who underwent allo-HSCT, observing that HIV reservoir depletion – independent of the donor’s CCR5 status – is mainly dependent on cell reduction during conditioning and on the GvR effect after full donor chimerism, resulting in a reservoir half-life of only several months. Although allo-HSCT is not a scalable strategy due to its complexity and high associated mortality, our results should throw light on several critical factors that could guide new strategies for achieving an HIV cure.

Supplementary Material

Appendix

RESEARCH IN CONTEXT.

Evidence before this study

The PubMed database was searched on October 25th 2023, for studies reporting cases of allo-HSCT in people with HIV (PWH) without any time limit or restriction of country, donor type or language (key words: allogeneic hematopoietic stem cell transplantation and HIV). Previous studies reported to this date that included virological data are: The Berlin patient, the two Boston patients, the Essen Patient, the three Australia patients, The Barcelona Patient (IciS-04), the London patient (IciS-36), the Dusseldorf patient (IciS-19), the New York patient, the two Netherland cases (IciS-5 and IciS-11), and the City of Hope patient. As observed, they are all individual case reports of allo-HSCT in PWH and hematological malignancies in whom potential long-term HIV remission or cure was considered, including partial data from the IciStem cohort. The largest data set previously published from this cohort included data from approximately half of the participants, but focused solely on T-cell characterization and functionality, without overlapping with the present manuscript. Previous cohort-based studies have assessed feasibility and safety of allogeneic hematopoietic cell transplant in PWH with only limited exploration of the impact on HIV persistence. Therefore, to date, there are no publications that deeply explore the dynamics of viral reservoir and antibody decline in a large prospective cohort of PWH (n=30) after allo-HSCT.

Added value of this study

This is the first study to report comprehensive prospective data on blood and tissue HIV reservoir dynamics collected over more than 8 years from 30 PWH undergoing allo-HSCT, all included in the IciStem Cohort. Indeed, this study presents new follow-up data and integrates multiple parameters to provide insights into the mechanisms contributing to the significant reduction of the HIV reservoir observed in the IciStem Cohort. Our results point to the allogeneic donor cell immunity as the main factor related to the reduction of the HIV reservoir. Complementary data on the quantity and quality of virus-specific antibodies during the transplant shows for the first time that the antibody decay lags behind the reduction of the HIV reservoir. The added value of having a large international cohort of participants is also reflected in the ability to model the dynamics of reservoir and antibodies, depletion, allowing us to estimate a reservoir half live of 1.5 months after allo-HSCT.

Implications of all the available evidence

Although allo-HSCT is not a scalable strategy for HIV cure due to its complexity and high associated mortality, our results shed light and may guide in the cases where allo-HSCT may be necessary due to a hematological malignance in PWH.

Acknowledgements

The authors thank the members of the IciStem Consortium (Appendix) for their support and discussion of the results. The authors would like to express their gratitude to all the participants included in the cohort and their generosity in helping the research and the community. The authors also thank Marco A. Fernández Sanmartín from the Flow Cytometry Service of the Germans Trias i Pujol Research Institute, Águeda Hernández Rodríguez, Victoria González Soler, Belén Rivaya Sánchez from the Microbiology Department of the University Hospital Germans Trias i Pujol, Juan Ambrosioni from the Hospital Clinic Barcelona, Jan van Lunzen from Hamburg University, and Rowena Johnston from amfAR.

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. CG was supported by the PhD fellowship of the Spanish Ministry of Education, Culture, and Sport (FPU15/03698). MS is supported by the Miguel Servet Fellowship Program (CP22/00038) and I+D+I RTI-A Grant (PID2020-115931RA-I00) from the Ministry of Science and Innovation. FC-O and JTS are supported by the US National Institutes of Health/National Institute for Allergy and Infectious Diseases (R01 AI150500). JSZW is supported by the German Center for Infection Research (DZIF TTU 04.816), the European Research Council (ERC H2020 grant 681032), the H.W. & J. Hector Stiftung (project M2101), the Hamburgische Investitions- und Förderbank (IFB Hamburg, PROFI Nr. 51167035) and the DFG -SFB1328 A12. Research in the JM-P lab is supported by the Spanish Ministry of Science and Innovation (grants PID2019-109870RB-I00 and CB21/13/00063), NIH/NIAID (1 UM1 AI164561-01 and 1P01AI178376-01), EU HORIZON-HLTH-2021-DISEASE-04-07 (grants 101057100 and 101095606), Fundació La Marató de TV3 (grant 202130-30-31-32), and Generalitat de València (grant PROMETEO/2021/036). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Footnotes

Declaration of interests: AB reports receiving grants from Gilead Sciences; and participating on the advisory board of ViiV Healthcare. AMJW reports receiving support to this manuscript from amfAR and Aidsfunds; grants from Gilead and NOW; consulting fees from ViiV Healthcare/GSK, MSD, Gilead Sciences; participating on the board of the Dutch Federation of Medical Microbiology, the board European Society for translational antiviral Research, chair on IAS-USA mutations workgroup, the Committee of ZonMW (Dutch research organization) Research and committee of Dutch federation for Long Covid; and receiving materials from Ark. ASC reports support to this manuscript from amfAR; receiving grants from ANRS, NIH, Institute Pasteur and MSDAVENIR; honoraria from lecture from MSD, ViiV healthcare and Gilead Sciences; and being chair of the Scientific and Medical committee of Sidaction. B-EOJ reports receiving consulting fees from Gilead Sciences, ViiV Healthcare and Merck Sharp & Dohme; honoraria for lectures from Gilead Sciences and ViiV Healtchare; support for attending meetings from Gilead; and being scientific secretary for the Germans AIDS society. BR reports receiving honoraria for lectures from Gilead Sciences, Janssen and ViiV Healthcare; payment for advice from ViiV Healthcare; and support for attending meetings and travel from ViiV Healthcare and Gilead Sciences. GH reports receiving support for attending the meeting and travel for the HIV Persistence Workshop 2022. JB reports receiving honoraria for lectures from AbbVie, Pfizer and Gilead Sciences; and support for attending meetings from AbbVie, Pfizer and Gilead Sciences. JK reports receiving grants from Novartis and Miltenyi Biotech; royalties from GADETA and Miltenyi Biotech; having a patent with GADETA; and holding stock interest in GADETA. JMP reports receiving support to this manuscript from amfAR. JSZW reports receiving support to this manuscript from The German Center for Infection Research, EU H2020 Research and Innovation Programme, H.W. & J. Hector Foundation, the German Research Foundation, The Hamburg Investment and Development Bank and amfAR; honoraria for lectures from Nobite, GSK and Gilead Sciences. JTS reports receiving support to this manuscript from NIH/NIAID. LS reports receiving grants from Abbvie and Gilead Sciences; consulting fees from Abbvie and Gilead Sciences; and honoraria for lectures from Abbvie and Gilead Sciences. LV reports receiving grants from ViiV Healthcare and Gilead Sciences; and consulting fees from ViiV Healthcare and Gilead Sciences. MJG and GA declare being an employee of Ragon Institute of MGH, MIT, and Harvard during the study; and an employee of Moderna afterwards. MN reports receiving consulting fees from Gilead Sciences; and honoraria for lectures from Viiv Healthcare. All other authors declare no conflicts of interests.

Data Sharing:

Study data will not be publicly available. Data can be made available by the corresponding author to any interested researcher following approval of a concept sheet summarizing the analysis to be done. Deidentified participant data and a data dictionary can be made available and shared under a data transfer agreement. Requests for access to the IciStem study data should be sent to msalgado@irsicaixa.es or jmpicado@irsicaixa.es.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Appendix
NIHMS2001014-supplement-Appendix.pdf (3.8MB, pdf)

Data Availability Statement

Study data will not be publicly available. Data can be made available by the corresponding author to any interested researcher following approval of a concept sheet summarizing the analysis to be done. Deidentified participant data and a data dictionary can be made available and shared under a data transfer agreement. Requests for access to the IciStem study data should be sent to msalgado@irsicaixa.es or jmpicado@irsicaixa.es.

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