THAA0101 - Oral Abstract Session
Long-term reduction in peripheral blood HIV-1 reservoirs following reduced-intensity conditioning allogeneic stem cell transplantation in two HIV-positive individuals
Presented by Timothy J. Henrich (United States).
T.J. Henrich1,2, G. Sciaranghella3, J.Z. Li1,2, S. Gallien4, V. Ho2,5, A.S. LaCasce2,5, D.R. Kuritzkes1,2
1Brigham and Women's Hospital, Boston, United States, 2Harvard Medical School, Boston, United States, 3Ragon Institute of MGH, MIT and Harvard, Boston, United States, 4Hopital Saint-Louis, Paris, France, 5Dana-Farber Cancer Institute, Boston, United States
Background: Functional HIV-1 cure has been described in the setting of myeloablative allogeneic stem cell transplant (alloSCT) with ccr5Δ32/ ccr5Δ32 donor cells, but the effects of alloSCT on viral reservoirs are largely unknown. We studied the longitudinal effects of reduced-intensity conditioning (RIC) alloSCT on HIV-1 peripheral blood reservoirs in two infected male patients with hematologic malignancies who previously underwent autologous SCT.
Methods: Analysis of peripheral HIV-1 reservoirs was performed on banked samples (1 pre- and 3 post-RIC-AlloSCT) for both patients, including: 1) quantification of HIV-1 DNA from peripheral blood mononuclear cells (PBMCs), 2) quantification of 2-LTR circles from PBMC episomal DNA, 3) full-length envelope amplification and phenotypic coreceptor usage prediction from proviral DNA, 4) quantification of plasma viremia by a single-copy assay, 5) flow cytometric characterization of lymphocyte subsets and coreceptor expression, and 6) CCR5 genotyping.
Results: No HIV-1 DNA was detected 8 to 17 months after alloSCT in PBMC from both patients despite presence of modest levels of total PBMC-associated HIV-1 DNA prior to and 2-3 months after SCT (87-271 copies/106 PBMCs). 2-LTR circles were not detected at any time-point despite excellent recovery of episomal mitochondrial DNA. Both patients were heterozygous for ccr5Δ32 mutation prior to transplant; a transient reduction in CXCR4 expression was observed following transplant. Pseudoviruses incorporating envelopes from early time-points used predominately CCR5 for entry. Both patients remained virologically suppressed on ART, but were either started on prednisone or continued on tacrolimus/sirolimus immunosuppressive therapy for chronic graft-versus-host disease (GVHD) near the time of loss of HIV-1 reservoir detection.
Conclusions: PBMC HIV-1 DNA became undetectable 8 months after RIC-alloSCT. This finding may be due to a dilutional effect of donor cell engraftment in the setting of protective ART, the additive effect of cytotoxic therapies, and/or GVHD. Confirmation of results by sampling large-volume blood collections and other tissue compartments is warranted.
[Quantification of Peripheral Blood HIV Reservoirs]
|Patient||Sample Collection Time (months from allogeneic SCT)||Total HIV-1 DNA (copies/million PBMCs)||2-LTR HIV-1 DNA (copies/million PBMCs)||Plasma HIV-1 RNA (copies/ml)|
|ND = Target Not Detected|
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