Evidence for persistence of the SHIV reservoir early after MHC haploidentical hematopoietic stem cell transplantation

Lucrezia Colonna; Christopher W. Peterson; John B. Schell; Judith M. Carlson; Victor Tkachev; Melanie Brown; Alison Yu; Sowmya Reddy; Willi M. Obenza; Veronica Nelson; Patricia S. Polacino; Heather Mack; Shiu Lok Hu; Katie Zeleski; Michelle Hoffman; Joe Olvera; Scott N. Furlan; Hengqi Zheng; Agne Taraseviciute; Daniel J. Hunt; Kayla Betz; Jennifer F. Lane; Keith Vogel; Charlotte E. Hotchkiss; Cassie Moats; Audrey Baldessari; Robert D. Murnane; Christopher English; Cliff A. Astley; Solomon Wangari; Brian Agricola; Joel Ahrens; Naoto Iwayama; Andrew May; Laurence Stensland; Meei Li W. Huang; Keith R. Jerome; Hans Peter Kiem; Leslie S. Kean

doi:10.1038/s41467-018-06736-7

Evidence for persistence of the SHIV reservoir early after MHC haploidentical hematopoietic stem cell transplantation

Lucrezia Colonna, Christopher W. Peterson, John B. Schell, Judith M. Carlson, Victor Tkachev, Melanie Brown, Alison Yu, Sowmya Reddy, Willi M. Obenza, Veronica Nelson, Patricia S. Polacino, Heather Mack, Shiu Lok Hu, Katie Zeleski, Michelle Hoffman, Joe Olvera, Scott N. Furlan, Hengqi Zheng, Agne Taraseviciute, Daniel J. HuntKayla Betz, Jennifer F. Lane, Keith Vogel, Charlotte E. Hotchkiss, Cassie Moats, Audrey Baldessari, Robert D. Murnane, Christopher English, Cliff A. Astley, Solomon Wangari, Brian Agricola, Joel Ahrens, Naoto Iwayama, Andrew May, Laurence Stensland, Meei Li W. Huang, Keith R. Jerome, Hans Peter Kiem, Leslie S. Kean

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11 Scopus citations

Abstract

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.

Original language	English (US)
Article number	4438
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-06736-7
State	Published - Dec 1 2018
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Colonna, L., Peterson, C. W., Schell, J. B., Carlson, J. M., Tkachev, V., Brown, M., Yu, A., Reddy, S., Obenza, W. M., Nelson, V., Polacino, P. S., Mack, H., Hu, S. L., Zeleski, K., Hoffman, M., Olvera, J., Furlan, S. N., Zheng, H., Taraseviciute, A., ... Kean, L. S. (2018). Evidence for persistence of the SHIV reservoir early after MHC haploidentical hematopoietic stem cell transplantation. Nature communications, 9(1), [4438]. https://doi.org/10.1038/s41467-018-06736-7

Colonna, L, Peterson, CW, Schell, JB, Carlson, JM, Tkachev, V, Brown, M, Yu, A, Reddy, S, Obenza, WM, Nelson, V, Polacino, PS, Mack, H, Hu, SL, Zeleski, K, Hoffman, M, Olvera, J, Furlan, SN, Zheng, H, Taraseviciute, A, Hunt, DJ, Betz, K, Lane, JF, Vogel, K, Hotchkiss, CE, Moats, C, Baldessari, A, Murnane, RD, English, C, Astley, CA, Wangari, S, Agricola, B, Ahrens, J, Iwayama, N, May, A, Stensland, L, Huang, MLW, Jerome, KR, Kiem, HP & Kean, LS 2018, 'Evidence for persistence of the SHIV reservoir early after MHC haploidentical hematopoietic stem cell transplantation', Nature communications, vol. 9, no. 1, 4438. https://doi.org/10.1038/s41467-018-06736-7

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title = "Evidence for persistence of the SHIV reservoir early after MHC haploidentical hematopoietic stem cell transplantation",

abstract = "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.",

author = "Lucrezia Colonna and Peterson, {Christopher W.} and Schell, {John B.} and Carlson, {Judith M.} and Victor Tkachev and Melanie Brown and Alison Yu and Sowmya Reddy and Obenza, {Willi M.} and Veronica Nelson and Polacino, {Patricia S.} and Heather Mack and Hu, {Shiu Lok} and Katie Zeleski and Michelle Hoffman and Joe Olvera and Furlan, {Scott N.} and Hengqi Zheng and Agne Taraseviciute and Hunt, {Daniel J.} and Kayla Betz and Lane, {Jennifer F.} and Keith Vogel and Hotchkiss, {Charlotte E.} and Cassie Moats and Audrey Baldessari and Murnane, {Robert D.} and Christopher English and Astley, {Cliff A.} and Solomon Wangari and Brian Agricola and Joel Ahrens and Naoto Iwayama and Andrew May and Laurence Stensland and Huang, {Meei Li W.} and Jerome, {Keith R.} and Kiem, {Hans Peter} and Kean, {Leslie S.}",

note = "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 Jos{\'e} Car-reras/E. Donnall Thomas Endowed Chair for Cancer Research and the Fred Hutch Endowed Chair for Cell and Gene Therapy. Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-06736-7",

language = "English (US)",

volume = "9",

journal = "Nature Communications",

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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).

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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Evidence for persistence of the SHIV reservoir early after MHC haploidentical hematopoietic stem cell transplantation

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