HIV-1 remission and possible cure in a woman after haplo-cord blood transplant

Abstract

Previously, two men were cured of HIV-1 through CCR5Δ32 homozygous (CCR5Δ32/Δ32) allogeneic adult stem cell transplant. We report the first remission and possible HIV-1 cure in a mixed-race woman who received a CCR5Δ32/Δ32 haplo-cord transplant (cord blood cells combined with haploidentical stem cells from an adult) to treat acute myeloid leukemia (AML). Peripheral blood chimerism was 100% CCR5Δ32/Δ32 cord blood by week 14 post-transplant and persisted through 4.8 years of follow-up. Immune reconstitution was associated with (1) loss of detectable replication-competent HIV-1 reservoirs, (2) loss of HIV-1-specific immune responses, (3) in vitro resistance to X4 and R5 laboratory variants, including pre-transplant autologous latent reservoir isolates, and (4) 18 months of HIV-1 control with aviremia, off antiretroviral therapy, starting at 37 months post-transplant. CCR5Δ32/Δ32 haplo-cord transplant achieved remission and a possible HIV-1 cure for a person of diverse ancestry, living with HIV-1, who required a stem cell transplant for acute leukemia.

Trial registration: ClinicalTrials.gov NCT02140944.

Keywords: HIV CCR5 dela 32 transplant; HIV cure; HIV remission.

Figure 1.. HIV-1 and AML Treatment Course and Rebound Monitoring

(A) HIV-1 plasma viral loads at HIV-1 diagnosis, before and after AML diagnosis, and stem cell transplant. The participant was enrolled in the P1107 trial at the time of stem cell transplant with HIV-1 control on ART. The blue line indicates the timing of antiretroviral treatment interruption (ATI) relative to the transplant. There was no viremic rebound off ART for 18 months. A clinical assay measured plasma viral load (VL) with a limit of detection of <20 copies/mL, indicated by the red line. At diagnosis, the HIV-1 VL was greater than the upper limit of quantitation (1,000,000 copies/mL), indicated by the green *. (B) Schema of the haplo-cord stem cell transplant. The participant received an allogeneic stem cell transplant per institutional standard care. Conditioning regimen was fludarabine 30mg/m² daily on Days −7 to −3, melphalan 140mg/m² x 1 dose (Day −2) and total body irradiation at 400 CGy on Days −7 to −6. Haploidentical stem cells were infused on D0, and CCR5 Δ32/Δ32 cord stem cells were infused on D+1. Graft versus host (GVH) disease prophylaxis included: antithymocyte globulin (ATG) 1.5 mg/kg on Days −5, −3, and −1, mycophenolate mofetil (MMF) one gram three times daily on Days −2 through Day +28, and tacrolimus from Day −2 to Day 180 post-transplant. (C) Clinical course, immune status pre-transplant, and post-transplant immune reconstitution. T-cells (CD4, CD8), B-cells (CD19), and natural killer (NK) cells (CD16/CD56) levels. Induction chemotherapy consisted of idarubicin/cytarabine (ida/cyt) and consolidation of one cycle of high-dose cytarabine chemotherapy. The first blue line shows the time of stem cell infusion after conditioning chemotherapy. Rituximab (375 mg/m2) was given one week before the conditioning regimen for prophylaxis of Epstein-Barr Virus (EBV) associated post-transplant lymphoproliferative disease. A second dose of rituximab was given for EBV viremia treatment. Rituximab resulted in transient undetectable CD19 levels before full recovery. ATI (second blue line), post-transplant immunizations (green arrows), and COVID-19 vaccinations with an mRNA vaccine (green arrows).

Figure 2:. Chimerism Dynamics Post Haplo-cord Stem Cell Transplant Over Time.

(A) Myeloid lineage chimerism was measured by CD33; (B) Lymphoid lineage chimerism was measured by CD3. By 14 weeks post-transplant, CD3 and CD33 chimerism were at 100% CCR5 Δ32/Δ32 CBU cells and maintained at four years post-transplant. Recipient (orange shaded), haploidentical donor (blue), and cord blood cells (gray) chimerism. The black line indicates the time change from weeks to years.

Figure 3.. Biomarkers of HIV-1 Persistence Pre-and Post-transplant.

(A) Plasma viral load (HIV-1 RNA copies/mL) quantified with a single-copy viral load assay; the limit of detection of the plasma viral load assay ranged from <0.5- to <0.9 HIV-1 RNA copies/mL). (B) Cell-associated HIV-1 DNA (copies/10⁶ cells) measured with a droplet digital PCR assay that detects to 1.25 copies/ 1 ×10⁶ cells analyzed with a limit of detection (concentration detected 95% of the time) of < 4.09 copies/10⁶ cells; (C) 2-LTR circles (copies/10⁶ cells) assayed with a droplet digital PCR assay; (D) Latent reservoir size determined by QVOA expressed as infectious units per million (IUPM) CD4+ T-cells. Closed and open symbols represent each biomarker’s detectable and non-detectable levels. The blue dashed line indicates ATI.

Figure 4.. In vitro HIV-1 Resistance.

(A) In vitro resistance of patient PBMC post-transplant Week 107 (red line) to CCR5-tropic (HIV-1-BAL) and CXCR4- tropic (HIV-1-NL4–3) compared to replication in healthy control PBMC (blue line), measured by p24 antigen in culture supernatants. (B) In vitro resistance of patient PBMC post-transplant Week 107 (red line) to the two autologous latent reservoir clones isolated pre-transplant (A & B) compared to replication in healthy control PBMC (blue line) as measured by p24 antigen in culture supernatants.

Figure 5.. HIV-1 Antibody Profiles by Western Blot.

HIV-1 proteins and molecular weights are indicated. Detectable HIV-1 antibodies are shown in high (++), low (+) positive and negative controls (neg) and antibody profiles at the entry into IMPAACT P1107 (Week 0) and several timepoints following haplo-cord transplant, including post-ATI. There was a loss of HIV-1 antibody responses by 52 weeks post-transplant and maintained even after ATI (red line).