Allogeneic immunity clears latent virus following allogeneic stem cell transplantation in SIV-infected ART-suppressed macaques

Helen L. Wu; Kathleen Busman-Sahay; Whitney C. Weber; Courtney M. Waytashek; Carla D. Boyle; Katherine B. Bateman; Jason S. Reed; Joseph M. Hwang; Christine Shriver-Munsch; Tonya Swanson; Mina Northrup; Kimberly Armantrout; Heidi Price; Mitch Robertson-LeVay; Samantha Uttke; Mithra R. Kumar; Emily J. Fray; Sol Taylor-Brill; Stephen Bondoc; Rebecca Agnor; Stephanie L. Junell; Alfred W. Legasse; Cassandra Moats; Rachele M. Bochart; Joseph Sciurba; Benjamin N. Bimber; Michelle N. Sullivan; Brandy Dozier; Rhonda P. MacAllister; Theodore R. Hobbs; Lauren D. Martin; Angela Panoskaltsis-Mortari; Lois M.A. Colgin; Robert F. Siliciano; Janet D. Siliciano; Jacob D. Estes; Jeremy V. Smedley; Michael K. Axthelm; Gabrielle Meyers; Richard T. Maziarz; Benjamin J. Burwitz; Jeffrey J. Stanton; Jonah B. Sacha

doi:10.1016/j.immuni.2023.04.019

Allogeneic immunity clears latent virus following allogeneic stem cell transplantation in SIV-infected ART-suppressed macaques

Helen L. Wu
, Kathleen Busman-Sahay
, Whitney C. Weber
, Courtney M. Waytashek
, Carla D. Boyle
, Katherine B. Bateman
, Jason S. Reed
, Joseph M. Hwang
, Christine Shriver-Munsch
, Tonya Swanson
, Mina Northrup
, Kimberly Armantrout
, Heidi Price
, Mitch Robertson-LeVay
, Samantha Uttke
, Mithra R. Kumar
, Emily J. Fray
, Sol Taylor-Brill
, Stephen Bondoc
, Rebecca Agnor

Stephanie L. Junell, Alfred W. Legasse, Cassandra Moats, Rachele M. Bochart, Joseph Sciurba, Benjamin N. Bimber, Michelle N. Sullivan, Brandy Dozier, Rhonda P. MacAllister, Theodore R. Hobbs, Lauren D. Martin, Angela Panoskaltsis-Mortari, Lois M.A. Colgin, Robert F. Siliciano, Janet D. Siliciano, Jacob D. Estes, Jeremy V. Smedley, Michael K. Axthelm, Gabrielle Meyers, Richard T. Maziarz, Benjamin J. Burwitz, Jeffrey J. Stanton, Jonah B. Sacha

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

Abstract

Allogeneic hematopoietic stem cell transplantation (alloHSCT) from donors lacking C-C chemokine receptor 5 (CCR5^Δ32/Δ32) can cure HIV, yet mechanisms remain speculative. To define how alloHSCT mediates HIV cure, we performed MHC-matched alloHSCT in SIV⁺, anti-retroviral therapy (ART)-suppressed Mauritian cynomolgus macaques (MCMs) and demonstrated that allogeneic immunity was the major driver of reservoir clearance, occurring first in peripheral blood, then peripheral lymph nodes, and finally in mesenteric lymph nodes draining the gastrointestinal tract. While allogeneic immunity could extirpate the latent viral reservoir and did so in two alloHSCT-recipient MCMs that remained aviremic >2.5 years after stopping ART, in other cases, it was insufficient without protection of engrafting cells afforded by CCR5-deficiency, as CCR5-tropic virus spread to donor CD4⁺ T cells despite full ART suppression. These data demonstrate the individual contributions of allogeneic immunity and CCR5 deficiency to HIV cure and support defining targets of alloimmunity for curative strategies independent of HSCT.

Original language	English (US)
Pages (from-to)	1649-1663.e5
Journal	Immunity
Volume	56
Issue number	7
DOIs	https://doi.org/10.1016/j.immuni.2023.04.019
State	Published - Jul 11 2023

Funding

We thank Amgen, Inc. for providing Neupogen, Bristol Myers Squibb for providing Nulojix, Gilead Sciences, Inc. for providing TDF and FTC, ViiV Healthcare for providing DTG, Brandon Keele for providing the SHIV-AD8-EOM virus, William Sutton and Nancy Haigwood for providing SIVmac239 gp140 trimer, and the ONPRC research support and animal care staff for their work with the study animals. We also wish to acknowledge the animals that contributed to this study and express our respect and gratitude for their invaluable role in this research. This work was supported by the National Institutes of Health grants AI112433 and AI129703 awarded to J.B.S. and P51 OD011092 awarded to the Oregon National Primate Research Center (ONPRC). The ONPRC Molecular Virology Support Core and Integrated Pathology Core provided support services for this research. This work was also supported by The Foundation for AIDS Research (amfAR) grant 108832 awarded to J.B.S. with support from Foundation for AIDS Immune Research (FAIR). Graphical abstract created with BioRender.com . We thank Amgen, Inc. for providing Neupogen, Bristol Myers Squibb for providing Nulojix, Gilead Sciences, Inc. for providing TDF and FTC, ViiV Healthcare for providing DTG, Brandon Keele for providing the SHIV-AD8-EOM virus, William Sutton and Nancy Haigwood for providing SIVmac239 gp140 trimer, and the ONPRC research support and animal care staff for their work with the study animals. We also wish to acknowledge the animals that contributed to this study and express our respect and gratitude for their invaluable role in this research. This work was supported by the National Institutes of Health grants AI112433 and AI129703 awarded to J.B.S. and P51 OD011092 awarded to the Oregon National Primate Research Center (ONPRC). The ONPRC Molecular Virology Support Core and Integrated Pathology Core provided support services for this research. This work was also supported by The Foundation for AIDS Research (amfAR) grant 108832 awarded to J.B.S. with support from Foundation for AIDS Immune Research (FAIR). Graphical abstract created with BioRender.com. Conceptualization, J.B.S.; methodology, H.L.W. K.B.-S. B.N.B. T.R.H. L.D.M. R.F.S. J.D.S. J.D.E. J.V.S. G.M. R.T.M. B.J.B. J.J.S. and J.B.S.; investigation, H.L.W. K.B.-S. W.C.W. C.M.W. C.D.B. K.B.B. J.S.R. J.M.H. C.S.-M. T.S. M.N. K.A. H.P. M.R.-L. S.U. M.R.K. E.J.F. S.T.-B. S.B. S.L.J. A.W.L. C.M. R.M.B. J.S. M.N.S. B.D. R.P.M. T.R.H. L.D.M. A.P.-M. L.M.A.C. J.V.S. M.K.A. G.M. R.T.M. and J.J.S.; formal analysis, H.L.W. and R.A.; writing – original draft, H.L.W.; writing – review & editing, H.L.W. and J.B.S.; visualization, H.L.W. and K.B.-S.; supervision, H.L.W. G.M. R.T.M. B.J.B. J.J.S. and J.B.S.; project administration, H.L.W. J.J.S. and J.B.S.; funding acquisition, J.B.S. J.B.S. has a significant financial interest in and serves on the scientific advisory board of CytoDyn, a company that may have a financial interest in the results of this research and technology. This potential individual conflict of interest has been reviewed and managed by OHSU. We support inclusive, diverse, and equitable conduct of research.

Funders	Funder number
CytoDyn Inc.
Fair Isaac Corporation
Foundation for AIDS Immune Research
Author National Institutes of Health National Institutes of Health National Institutes of Health National Institutes of Health The Bev Hartig Huntington's Disease Foundation National Institutes of Health	AI112433, AI129703, P51 OD011092
amfAR, The Foundation for AIDS Research	108832
Amgen
Oregon State University/Oregon Health and Science University
Oregon National Primate Research Center

Keywords

CCR5
GVHD
HIV
HSCT
SIV

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

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10.1016/j.immuni.2023.04.019

Cite this

Wu, H. L., Busman-Sahay, K., Weber, W. C., Waytashek, C. M., Boyle, C. D., Bateman, K. B., Reed, J. S., Hwang, J. M., Shriver-Munsch, C., Swanson, T., Northrup, M., Armantrout, K., Price, H., Robertson-LeVay, M., Uttke, S., Kumar, M. R., Fray, E. J., Taylor-Brill, S., Bondoc, S., ... Sacha, J. B. (2023). Allogeneic immunity clears latent virus following allogeneic stem cell transplantation in SIV-infected ART-suppressed macaques. Immunity, 56(7), 1649-1663.e5. https://doi.org/10.1016/j.immuni.2023.04.019

Wu, HL, Busman-Sahay, K, Weber, WC, Waytashek, CM, Boyle, CD, Bateman, KB, Reed, JS, Hwang, JM, Shriver-Munsch, C, Swanson, T, Northrup, M, Armantrout, K, Price, H, Robertson-LeVay, M, Uttke, S, Kumar, MR, Fray, EJ, Taylor-Brill, S, Bondoc, S, Agnor, R, Junell, SL, Legasse, AW, Moats, C, Bochart, RM , Sciurba, J , Bimber, BN, Sullivan, MN, Dozier, B , MacAllister, RP , Hobbs, TR , Martin, LD, Panoskaltsis-Mortari, A, Colgin, LMA, Siliciano, RF, Siliciano, JD, Estes, JD, Smedley, JV, Axthelm, MK , Meyers, G , Maziarz, RT , Burwitz, BJ , Stanton, JJ & Sacha, JB 2023, 'Allogeneic immunity clears latent virus following allogeneic stem cell transplantation in SIV-infected ART-suppressed macaques', Immunity, vol. 56, no. 7, pp. 1649-1663.e5. https://doi.org/10.1016/j.immuni.2023.04.019

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title = "Allogeneic immunity clears latent virus following allogeneic stem cell transplantation in SIV-infected ART-suppressed macaques",

abstract = "Allogeneic hematopoietic stem cell transplantation (alloHSCT) from donors lacking C-C chemokine receptor 5 (CCR5Δ32/Δ32) can cure HIV, yet mechanisms remain speculative. To define how alloHSCT mediates HIV cure, we performed MHC-matched alloHSCT in SIV+, anti-retroviral therapy (ART)-suppressed Mauritian cynomolgus macaques (MCMs) and demonstrated that allogeneic immunity was the major driver of reservoir clearance, occurring first in peripheral blood, then peripheral lymph nodes, and finally in mesenteric lymph nodes draining the gastrointestinal tract. While allogeneic immunity could extirpate the latent viral reservoir and did so in two alloHSCT-recipient MCMs that remained aviremic >2.5 years after stopping ART, in other cases, it was insufficient without protection of engrafting cells afforded by CCR5-deficiency, as CCR5-tropic virus spread to donor CD4+ T cells despite full ART suppression. These data demonstrate the individual contributions of allogeneic immunity and CCR5 deficiency to HIV cure and support defining targets of alloimmunity for curative strategies independent of HSCT.",

keywords = "CCR5, GVHD, HIV, HSCT, SIV",

author = "Wu, \{Helen L.\} and Kathleen Busman-Sahay and Weber, \{Whitney C.\} and Waytashek, \{Courtney M.\} and Boyle, \{Carla D.\} and Bateman, \{Katherine B.\} and Reed, \{Jason S.\} and Hwang, \{Joseph M.\} and Christine Shriver-Munsch and Tonya Swanson and Mina Northrup and Kimberly Armantrout and Heidi Price and Mitch Robertson-LeVay and Samantha Uttke and Kumar, \{Mithra R.\} and Fray, \{Emily J.\} and Sol Taylor-Brill and Stephen Bondoc and Rebecca Agnor and Junell, \{Stephanie L.\} and Legasse, \{Alfred W.\} and Cassandra Moats and Bochart, \{Rachele M.\} and Joseph Sciurba and Bimber, \{Benjamin N.\} and Sullivan, \{Michelle N.\} and Brandy Dozier and MacAllister, \{Rhonda P.\} and Hobbs, \{Theodore R.\} and Martin, \{Lauren D.\} and Angela Panoskaltsis-Mortari and Colgin, \{Lois M.A.\} and Siliciano, \{Robert F.\} and Siliciano, \{Janet D.\} and Estes, \{Jacob D.\} and Smedley, \{Jeremy V.\} and Axthelm, \{Michael K.\} and Gabrielle Meyers and Maziarz, \{Richard T.\} and Burwitz, \{Benjamin J.\} and Stanton, \{Jeffrey J.\} and Sacha, \{Jonah B.\}",

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month = jul,

day = "11",

doi = "10.1016/j.immuni.2023.04.019",

language = "English (US)",

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T1 - Allogeneic immunity clears latent virus following allogeneic stem cell transplantation in SIV-infected ART-suppressed macaques

AU - Wu, Helen L.

AU - Busman-Sahay, Kathleen

AU - Weber, Whitney C.

AU - Waytashek, Courtney M.

AU - Boyle, Carla D.

AU - Bateman, Katherine B.

AU - Reed, Jason S.

AU - Hwang, Joseph M.

AU - Shriver-Munsch, Christine

AU - Swanson, Tonya

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AU - Armantrout, Kimberly

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AU - Uttke, Samantha

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AU - Taylor-Brill, Sol

AU - Bondoc, Stephen

AU - Agnor, Rebecca

AU - Junell, Stephanie L.

AU - Legasse, Alfred W.

AU - Moats, Cassandra

AU - Bochart, Rachele M.

AU - Sciurba, Joseph

AU - Bimber, Benjamin N.

AU - Sullivan, Michelle N.

AU - Dozier, Brandy

AU - MacAllister, Rhonda P.

AU - Hobbs, Theodore R.

AU - Martin, Lauren D.

AU - Panoskaltsis-Mortari, Angela

AU - Colgin, Lois M.A.

AU - Siliciano, Robert F.

AU - Siliciano, Janet D.

AU - Estes, Jacob D.

AU - Smedley, Jeremy V.

AU - Axthelm, Michael K.

AU - Meyers, Gabrielle

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AU - Stanton, Jeffrey J.

AU - Sacha, Jonah B.

PY - 2023/7/11

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N2 - Allogeneic hematopoietic stem cell transplantation (alloHSCT) from donors lacking C-C chemokine receptor 5 (CCR5Δ32/Δ32) can cure HIV, yet mechanisms remain speculative. To define how alloHSCT mediates HIV cure, we performed MHC-matched alloHSCT in SIV+, anti-retroviral therapy (ART)-suppressed Mauritian cynomolgus macaques (MCMs) and demonstrated that allogeneic immunity was the major driver of reservoir clearance, occurring first in peripheral blood, then peripheral lymph nodes, and finally in mesenteric lymph nodes draining the gastrointestinal tract. While allogeneic immunity could extirpate the latent viral reservoir and did so in two alloHSCT-recipient MCMs that remained aviremic >2.5 years after stopping ART, in other cases, it was insufficient without protection of engrafting cells afforded by CCR5-deficiency, as CCR5-tropic virus spread to donor CD4+ T cells despite full ART suppression. These data demonstrate the individual contributions of allogeneic immunity and CCR5 deficiency to HIV cure and support defining targets of alloimmunity for curative strategies independent of HSCT.

AB - Allogeneic hematopoietic stem cell transplantation (alloHSCT) from donors lacking C-C chemokine receptor 5 (CCR5Δ32/Δ32) can cure HIV, yet mechanisms remain speculative. To define how alloHSCT mediates HIV cure, we performed MHC-matched alloHSCT in SIV+, anti-retroviral therapy (ART)-suppressed Mauritian cynomolgus macaques (MCMs) and demonstrated that allogeneic immunity was the major driver of reservoir clearance, occurring first in peripheral blood, then peripheral lymph nodes, and finally in mesenteric lymph nodes draining the gastrointestinal tract. While allogeneic immunity could extirpate the latent viral reservoir and did so in two alloHSCT-recipient MCMs that remained aviremic >2.5 years after stopping ART, in other cases, it was insufficient without protection of engrafting cells afforded by CCR5-deficiency, as CCR5-tropic virus spread to donor CD4+ T cells despite full ART suppression. These data demonstrate the individual contributions of allogeneic immunity and CCR5 deficiency to HIV cure and support defining targets of alloimmunity for curative strategies independent of HSCT.

KW - CCR5

KW - GVHD

KW - HIV

KW - HSCT

KW - SIV

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UR - https://www.scopus.com/pages/publications/85163166868#tab=citedBy

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C2 - 37236188

AN - SCOPUS:85163166868

SN - 1074-7613

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SP - 1649-1663.e5

JO - Immunity

JF - Immunity

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ER -

Allogeneic immunity clears latent virus following allogeneic stem cell transplantation in SIV-infected ART-suppressed macaques

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