WELBA05 - Oral Abstract
In depth investigation of peripheral and gut HIV-1 reservoirs, HIV-specific cellular immunity, and host microchimerism following allogeneic hematopoetic stem cell transplantation
Presented by Timothy Henrich (United States).
T. Henrich1,2, E. Hanhauser1, M. Sirignano3, B. Davis2,3, T.-H. Lee4,5, S. Keating4,5, M. Busch4,5, F. Marty1,2,6, A. LaCasce2,6, P. Armand2,6, R. Soiffer2,6, M. Altfeld2,3,7, D. Kuritzkes1,2
1Brigham and Women's Hospital, Boston, United States, 2Harvard Medical School, Boston, United States, 3Massachusetts General Hospital, Boston, United States, 4Blood Systems Research Institute, San Francisco, United States, 5University of California, San Francisco, San Francisco, United States, 6Dana-Farber Cancer Institute, Boston, United States, 7Ragon Institute of MGH, Harvard & MIT, Cambridge, United States
Background: We previously reported the loss of detectable peripheral blood HIV-1 reservoirs in 2 individuals following reduced-intensity conditioning allogeneic hematopoetic stem cell transplantation (RIC-alloHSCT) from wild-type CCR5 donors. To understand further the impact of alloHSCT on viral reservoirs, we studied the longitudinal effects of HSCT on host microchimerism and HIV-specific cellular immunity, and tested rectal tissue and peripheral blood mononuclear cells (PBMCs) obtained by leukapheresis for evidence of residual HIV-1 DNA or replication-competent proviruses up to 4.3 years post-transplantation.
Methods: The following experiments were performed: 1) collection of PBMCs by leukapheresis for large-scale HIV-1 quantification of genomic DNA and viral co-culture from purified CD4+ T lymphocytes (assays using 5 million PBMCs were repeated up to 30 times for each patient), 2) HIV-1 DNA PCR on rectal tissue (one patient), and 3) microchimerism studies of residual donor PBMCs. We also investigated HIV-specific cellular immune function by ELISpot IFN-gamma screenings of total PBMCs involving comprehensive HLA-specific peptide panels on the above patients in addition to a third RIC-alloHSCT patient that died 6 months post-transplantation from recurrent lymphoma; a fourth patient who received an autologous HSCT served as a control.
Results: No HIV-1 DNA was detected from PBMCs from both previously-reported RIC-alloHSCT patients indicating at least a 3 to 4 log10 decrease in peripheral viral reservoir size post-transplantation. No HIV-1 p24 antigen was detected by viral co-culture from purified CD4+ T cells, and no HIV-1 DNA was detected in rectal tissue. Residual host cells constituted less than 0.001% of PBMCs post-HSCT and may have represented circulating non-hematopoietic cells. No HLA-specific or pooled HIV-1 peptides elicited a strong HIV-specific immune response from all patients either before or after allogeneic or autologous HSCT.
Conclusion: HIV-1 remained undetectable from peripheral blood and rectal tissue after RIC-alloHSCT in patients on ART despite the testing of very large numbers of PBMCs or CD4+ T cells. The lack of detectable HIV-1 was in the setting of full donor chimerism and weak HIV-specific cellular immunity. Analytical treatment interruption remains the definitive experiment to test the full impact of RIC-alloHSCT on HIV-1 persistence.
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