TY - JOUR
T1 - Evidence for persistence of the SHIV reservoir early after MHC haploidentical hematopoietic stem cell transplantation
AU - Colonna, Lucrezia
AU - Peterson, Christopher W.
AU - Schell, John B.
AU - Carlson, Judith M.
AU - Tkachev, Victor
AU - Brown, Melanie
AU - Yu, Alison
AU - Reddy, Sowmya
AU - Obenza, Willi M.
AU - Nelson, Veronica
AU - Polacino, Patricia S.
AU - Mack, Heather
AU - Hu, Shiu Lok
AU - Zeleski, Katie
AU - Hoffman, Michelle
AU - Olvera, Joe
AU - Furlan, Scott N.
AU - Zheng, Hengqi
AU - Taraseviciute, Agne
AU - Hunt, Daniel J.
AU - Betz, Kayla
AU - Lane, Jennifer F.
AU - Vogel, Keith
AU - Hotchkiss, Charlotte E.
AU - Moats, Cassie
AU - Baldessari, Audrey
AU - Murnane, Robert D.
AU - English, Christopher
AU - Astley, Cliff A.
AU - Wangari, Solomon
AU - Agricola, Brian
AU - Ahrens, Joel
AU - Iwayama, Naoto
AU - May, Andrew
AU - Stensland, Laurence
AU - Huang, Meei Li W.
AU - Jerome, Keith R.
AU - Kiem, Hans Peter
AU - Kean, Leslie S.
N1 - Funding Information:
We thank Ruth Ruprecht for the SHIV-C inoculum, Gilead and Merck for cART drugs and the Virology Core personnel, Bing Mei and Baoping Tian at the WaNPCR for assistance with viral load and serology assays. We thank the NIH Tetramer Core Facility for the kind provision of A01-CM9 tetramers. This study was supported by grants from the National Institutes of Health, National Institute of Allergy and Infectious Diseases (U19 AI096111 and UM1 AI126623 to HPK and KRJ, U19-AI051731, AI116184, and UM1AI126617 to LSK), National Heart, Lung, and Blood Institute (R01 HL116217 and U19 HL129902 to HPK and LSK and R01HL095791 to LSK). HPK is a Markey Molecular Medicine Investigator and received support as the inaugural recipient of the José Car-reras/E. Donnall Thomas Endowed Chair for Cancer Research and the Fred Hutch Endowed Chair for Cell and Gene Therapy.
Publisher Copyright:
© 2018, The Author(s).
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Allogeneic transplantation (allo-HCT) has led to the cure of HIV in one individual, raising the question of whether transplantation can eradicate the HIV reservoir. To test this, we here present a model of allo-HCT in SHIV-infected, cART-suppressed nonhuman primates. We infect rhesus macaques with SHIV-1157ipd3N4, suppress them with cART, then transplant them using MHC-haploidentical allogeneic donors during continuous cART. Transplant results in ~100% myeloid donor chimerism, and up to 100% T-cell chimerism. Between 9 and 47 days post-transplant, terminal analysis shows that while cell-associated SHIV DNA levels are reduced in the blood and in lymphoid organs post-transplant, the SHIV reservoir persists in multiple organs, including the brain. Sorting of donor-vs.-recipient cells reveals that this reservoir resides in recipient cells. Moreover, tetramer analysis indicates a lack of virus-specific donor immunity post-transplant during continuous cART. These results suggest that early post-transplant, allo-HCT is insufficient for recipient reservoir eradication despite high-level donor chimerism and GVHD.
AB - Allogeneic transplantation (allo-HCT) has led to the cure of HIV in one individual, raising the question of whether transplantation can eradicate the HIV reservoir. To test this, we here present a model of allo-HCT in SHIV-infected, cART-suppressed nonhuman primates. We infect rhesus macaques with SHIV-1157ipd3N4, suppress them with cART, then transplant them using MHC-haploidentical allogeneic donors during continuous cART. Transplant results in ~100% myeloid donor chimerism, and up to 100% T-cell chimerism. Between 9 and 47 days post-transplant, terminal analysis shows that while cell-associated SHIV DNA levels are reduced in the blood and in lymphoid organs post-transplant, the SHIV reservoir persists in multiple organs, including the brain. Sorting of donor-vs.-recipient cells reveals that this reservoir resides in recipient cells. Moreover, tetramer analysis indicates a lack of virus-specific donor immunity post-transplant during continuous cART. These results suggest that early post-transplant, allo-HCT is insufficient for recipient reservoir eradication despite high-level donor chimerism and GVHD.
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U2 - 10.1038/s41467-018-06736-7
DO - 10.1038/s41467-018-06736-7
M3 - Article
C2 - 30361514
AN - SCOPUS:85055452335
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 4438
ER -