Transient T Cell Expansion, Activation, and Proliferation in Therapeutically Vaccinated Simian Immunodeficiency Virus-Positive Macaques Treated with N-803

Olivia E. Harwood; Alexis J. Balgeman; Abigail J. Weaver; Amy L. Ellis-Connell; Andrea M. Weiler; Katrina N. Erickson; Lea M. Matschke; Athena E. Golfinos; Vaiva Vezys; Pamela J. Skinner; Jeffrey T. Safrit; Paul T. Edlefsen; Matthew R. Reynolds; Thomas C. Friedrich; Shelby L. O’Connor

doi:10.1128/jvi.01424-22

Transient T Cell Expansion, Activation, and Proliferation in Therapeutically Vaccinated Simian Immunodeficiency Virus-Positive Macaques Treated with N-803

Olivia E. Harwood, Alexis J. Balgeman, Abigail J. Weaver, Amy L. Ellis-Connell, Andrea M. Weiler, Katrina N. Erickson, Lea M. Matschke, Athena E. Golfinos, Vaiva Vezys, Pamela J. Skinner, Jeffrey T. Safrit, Paul T. Edlefsen, Matthew R. Reynolds, Thomas C. Friedrich, Shelby L. O’Connor

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

1 Scopus citations

Abstract

Vaccine strategies aimed at eliciting human immunodeficiency virus (HIV)-specific CD8¹ T cells are one major target of interest in HIV functional cure strategies. We hypothesized that CD8¹ T cells elicited by therapeutic vaccination during antiretroviral therapy (ART) would be recalled and boosted by treatment with the interleukin 15 (IL-15) superagonist N-803 after ART discontinuation. We intravenously immunized four simian immunodeficiency virus-positive (SIV¹) Mauritian cynomolgus macaques receiving ART with vesicular stomatitis virus (VSV), modified vaccinia virus Ankara strain (MVA), and recombinant adenovirus serotype 5 (rAd-5) vectors all expressing SIVmac239 Gag. Immediately after ART cessation, these animals received three doses of N-803. Four control animals received no vaccines or N-803. The vaccine regimen generated a high-magnitude response involving Gag-specific CD8¹ T cells that were proliferative and biased toward an effector memory phenotype. We then compared cells elicited by vaccination (Gag specific) to cells elicited by SIV infection and unaffected by vaccination (Nef specific). We found that N-803 treatment enhanced the frequencies of both bulk and proliferating antigen-specific CD8¹ T cells elicited by vaccination and the antigen-specific CD8¹ T cells elicited by SIV infection. In sum, we demonstrate that a therapeutic heterologous prime-boost-boost (HPBB) vaccine can elicit antigen-specific effector memory CD8¹ T cells that are boosted by N-803.

Original language	English (US)
Journal	Journal of virology
Volume	96
Issue number	23
DOIs	https://doi.org/10.1128/jvi.01424-22
State	Published - Dec 2022

Bibliographical note

Funding Information:
SIVmac239M was generously provided by Brandon Keele (Frederick National Laboratory for Cancer Research, Frederick, MD). DTG was graciously provided by ViiV Healthcare (Research Triangle, NC). TDF and FTC were graciously provided by Gilead (Foster City, CA). MVA was generously provided by Bernard Moss (NIH/NIAID). N-803 was generously provided by ImmunityBio (Culver City, CA). The following reagent was obtained through the NIH HIV Reagent Program, Division of AIDS, NIAID, NIH: peptide pool, simian immunodeficiency virus (SIV)mac239 Gag protein, ARP-12364, contributed by DAIDS/NIAID. We thank the NIH Tetramer Core Facility (contract number 75N93020D00005) for generating the Mafa-A1*063 Gag386-394GW9 and Mafa-A1*063 Nef103-111RM9 biotinylated monomers. We are grateful to the WNPRC staff for the exceptional veterinary care provided to the animals throughout this study.

Funding Information:
SIVmac239M was generously provided by Brandon Keele (Frederick National Laboratory for Cancer Research, Frederick, MD). DTG was graciously provided by ViiV Healthcare (Research Triangle, NC). TDF and FTC were graciously provided by Gilead (Foster City, CA). MVA was generously provided by Bernard Moss (NIH/NIAID). N-803 was generously provided by ImmunityBio (Culver City, CA). The following reagent was obtained through the NIH HIV Reagent Program, Division of AIDS, NIAID, NIH: peptide pool, simian immunodeficiency virus (SIV)mac239 Gag protein, ARP-12364, contributed by DAIDS/NIAID. We thank the NIH Tetramer Core Facility (contract number 75N93020D00005) for generating the Mafa-A1*063 Gag386-394GW9 and Mafa-A1*063 Nef103-111RM9 biotinylated monomers. We are grateful to the WNPRC staff for the exceptional veterinary care provided to the animals throughout this study. The Wisconsin National Primate Research Center is supported by grants P51RR000167 and P51OD011106. This study was funded through the National Institutes of Health (NIH R01 AI108415). Jeffrey T. Safrit is an employee of ImmunityBio, Inc. Pamela J. Skinner is a cofounder and CSO of MarPam Pharma LLC. O.E.H., A.L.E.-C., V.V., P.J.S., and S.L.O. contributed to the conception and design of the experiments. M.R.R., T.C.F., and S.L.O. provided supervision and reviewed data. O.E.H., A.J.B., A.J.W., A.M.W., K.N.E., L.M.M., and A.E.G. conducted experiments. O.E.H., A.L.E.-C., L.M.M., and P.T.E. analyzed the data. V.V. and J.T.S. provided key reagents. O.E.H. and S.L.O. wrote the manuscript.

Funding Information:
The Wisconsin National Primate Research Center is supported by grants P51RR000167 and P51OD011106. This study was funded through the National Institutes of Health (NIH R01 AI108415).

Publisher Copyright:
© 2022 American Society fo Microbiology. All Rights Reserved.

Keywords

ART
N-803
SIV
heterologous prime-boost-boost vaccination
nonhuman primate

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1128/jvi.01424-22

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Harwood, O. E., Balgeman, A. J., Weaver, A. J., Ellis-Connell, A. L., Weiler, A. M., Erickson, K. N., Matschke, L. M., Golfinos, A. E., Vezys, V., Skinner, P. J., Safrit, J. T., Edlefsen, P. T., Reynolds, M. R., Friedrich, T. C., & O’Connor, S. L. (2022). Transient T Cell Expansion, Activation, and Proliferation in Therapeutically Vaccinated Simian Immunodeficiency Virus-Positive Macaques Treated with N-803. Journal of virology, 96(23). https://doi.org/10.1128/jvi.01424-22

Harwood, OE, Balgeman, AJ, Weaver, AJ, Ellis-Connell, AL, Weiler, AM, Erickson, KN, Matschke, LM, Golfinos, AE, Vezys, V , Skinner, PJ, Safrit, JT, Edlefsen, PT, Reynolds, MR, Friedrich, TC & O’Connor, SL 2022, 'Transient T Cell Expansion, Activation, and Proliferation in Therapeutically Vaccinated Simian Immunodeficiency Virus-Positive Macaques Treated with N-803', Journal of virology, vol. 96, no. 23. https://doi.org/10.1128/jvi.01424-22

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title = "Transient T Cell Expansion, Activation, and Proliferation in Therapeutically Vaccinated Simian Immunodeficiency Virus-Positive Macaques Treated with N-803",

abstract = "Vaccine strategies aimed at eliciting human immunodeficiency virus (HIV)-specific CD81 T cells are one major target of interest in HIV functional cure strategies. We hypothesized that CD81 T cells elicited by therapeutic vaccination during antiretroviral therapy (ART) would be recalled and boosted by treatment with the interleukin 15 (IL-15) superagonist N-803 after ART discontinuation. We intravenously immunized four simian immunodeficiency virus-positive (SIV1) Mauritian cynomolgus macaques receiving ART with vesicular stomatitis virus (VSV), modified vaccinia virus Ankara strain (MVA), and recombinant adenovirus serotype 5 (rAd-5) vectors all expressing SIVmac239 Gag. Immediately after ART cessation, these animals received three doses of N-803. Four control animals received no vaccines or N-803. The vaccine regimen generated a high-magnitude response involving Gag-specific CD81 T cells that were proliferative and biased toward an effector memory phenotype. We then compared cells elicited by vaccination (Gag specific) to cells elicited by SIV infection and unaffected by vaccination (Nef specific). We found that N-803 treatment enhanced the frequencies of both bulk and proliferating antigen-specific CD81 T cells elicited by vaccination and the antigen-specific CD81 T cells elicited by SIV infection. In sum, we demonstrate that a therapeutic heterologous prime-boost-boost (HPBB) vaccine can elicit antigen-specific effector memory CD81 T cells that are boosted by N-803.",

keywords = "ART, N-803, SIV, heterologous prime-boost-boost vaccination, nonhuman primate",

author = "Harwood, {Olivia E.} and Balgeman, {Alexis J.} and Weaver, {Abigail J.} and Ellis-Connell, {Amy L.} and Weiler, {Andrea M.} and Erickson, {Katrina N.} and Matschke, {Lea M.} and Golfinos, {Athena E.} and Vaiva Vezys and Skinner, {Pamela J.} and Safrit, {Jeffrey T.} and Edlefsen, {Paul T.} and Reynolds, {Matthew R.} and Friedrich, {Thomas C.} and O{\textquoteright}Connor, {Shelby L.}",

note = "Funding Information: SIVmac239M was generously provided by Brandon Keele (Frederick National Laboratory for Cancer Research, Frederick, MD). DTG was graciously provided by ViiV Healthcare (Research Triangle, NC). TDF and FTC were graciously provided by Gilead (Foster City, CA). MVA was generously provided by Bernard Moss (NIH/NIAID). N-803 was generously provided by ImmunityBio (Culver City, CA). The following reagent was obtained through the NIH HIV Reagent Program, Division of AIDS, NIAID, NIH: peptide pool, simian immunodeficiency virus (SIV)mac239 Gag protein, ARP-12364, contributed by DAIDS/NIAID. We thank the NIH Tetramer Core Facility (contract number 75N93020D00005) for generating the Mafa-A1*063 Gag386-394GW9 and Mafa-A1*063 Nef103-111RM9 biotinylated monomers. We are grateful to the WNPRC staff for the exceptional veterinary care provided to the animals throughout this study. Funding Information: SIVmac239M was generously provided by Brandon Keele (Frederick National Laboratory for Cancer Research, Frederick, MD). DTG was graciously provided by ViiV Healthcare (Research Triangle, NC). TDF and FTC were graciously provided by Gilead (Foster City, CA). MVA was generously provided by Bernard Moss (NIH/NIAID). N-803 was generously provided by ImmunityBio (Culver City, CA). The following reagent was obtained through the NIH HIV Reagent Program, Division of AIDS, NIAID, NIH: peptide pool, simian immunodeficiency virus (SIV)mac239 Gag protein, ARP-12364, contributed by DAIDS/NIAID. We thank the NIH Tetramer Core Facility (contract number 75N93020D00005) for generating the Mafa-A1*063 Gag386-394GW9 and Mafa-A1*063 Nef103-111RM9 biotinylated monomers. We are grateful to the WNPRC staff for the exceptional veterinary care provided to the animals throughout this study. The Wisconsin National Primate Research Center is supported by grants P51RR000167 and P51OD011106. This study was funded through the National Institutes of Health (NIH R01 AI108415). Jeffrey T. Safrit is an employee of ImmunityBio, Inc. Pamela J. Skinner is a cofounder and CSO of MarPam Pharma LLC. O.E.H., A.L.E.-C., V.V., P.J.S., and S.L.O. contributed to the conception and design of the experiments. M.R.R., T.C.F., and S.L.O. provided supervision and reviewed data. O.E.H., A.J.B., A.J.W., A.M.W., K.N.E., L.M.M., and A.E.G. conducted experiments. O.E.H., A.L.E.-C., L.M.M., and P.T.E. analyzed the data. V.V. and J.T.S. provided key reagents. O.E.H. and S.L.O. wrote the manuscript. Funding Information: The Wisconsin National Primate Research Center is supported by grants P51RR000167 and P51OD011106. This study was funded through the National Institutes of Health (NIH R01 AI108415). Publisher Copyright: {\textcopyright} 2022 American Society fo Microbiology. All Rights Reserved.",

year = "2022",

month = dec,

doi = "10.1128/jvi.01424-22",

language = "English (US)",

volume = "96",

journal = "Journal of virology",

issn = "0022-538X",

publisher = "American Society for Microbiology",

number = "23",

}

TY - JOUR

T1 - Transient T Cell Expansion, Activation, and Proliferation in Therapeutically Vaccinated Simian Immunodeficiency Virus-Positive Macaques Treated with N-803

AU - Harwood, Olivia E.

AU - Balgeman, Alexis J.

AU - Weaver, Abigail J.

AU - Ellis-Connell, Amy L.

AU - Weiler, Andrea M.

AU - Erickson, Katrina N.

AU - Matschke, Lea M.

AU - Golfinos, Athena E.

AU - Vezys, Vaiva

AU - Skinner, Pamela J.

AU - Safrit, Jeffrey T.

AU - Edlefsen, Paul T.

AU - Reynolds, Matthew R.

AU - Friedrich, Thomas C.

AU - O’Connor, Shelby L.

N1 - Funding Information: SIVmac239M was generously provided by Brandon Keele (Frederick National Laboratory for Cancer Research, Frederick, MD). DTG was graciously provided by ViiV Healthcare (Research Triangle, NC). TDF and FTC were graciously provided by Gilead (Foster City, CA). MVA was generously provided by Bernard Moss (NIH/NIAID). N-803 was generously provided by ImmunityBio (Culver City, CA). The following reagent was obtained through the NIH HIV Reagent Program, Division of AIDS, NIAID, NIH: peptide pool, simian immunodeficiency virus (SIV)mac239 Gag protein, ARP-12364, contributed by DAIDS/NIAID. We thank the NIH Tetramer Core Facility (contract number 75N93020D00005) for generating the Mafa-A1*063 Gag386-394GW9 and Mafa-A1*063 Nef103-111RM9 biotinylated monomers. We are grateful to the WNPRC staff for the exceptional veterinary care provided to the animals throughout this study. Funding Information: SIVmac239M was generously provided by Brandon Keele (Frederick National Laboratory for Cancer Research, Frederick, MD). DTG was graciously provided by ViiV Healthcare (Research Triangle, NC). TDF and FTC were graciously provided by Gilead (Foster City, CA). MVA was generously provided by Bernard Moss (NIH/NIAID). N-803 was generously provided by ImmunityBio (Culver City, CA). The following reagent was obtained through the NIH HIV Reagent Program, Division of AIDS, NIAID, NIH: peptide pool, simian immunodeficiency virus (SIV)mac239 Gag protein, ARP-12364, contributed by DAIDS/NIAID. We thank the NIH Tetramer Core Facility (contract number 75N93020D00005) for generating the Mafa-A1*063 Gag386-394GW9 and Mafa-A1*063 Nef103-111RM9 biotinylated monomers. We are grateful to the WNPRC staff for the exceptional veterinary care provided to the animals throughout this study. The Wisconsin National Primate Research Center is supported by grants P51RR000167 and P51OD011106. This study was funded through the National Institutes of Health (NIH R01 AI108415). Jeffrey T. Safrit is an employee of ImmunityBio, Inc. Pamela J. Skinner is a cofounder and CSO of MarPam Pharma LLC. O.E.H., A.L.E.-C., V.V., P.J.S., and S.L.O. contributed to the conception and design of the experiments. M.R.R., T.C.F., and S.L.O. provided supervision and reviewed data. O.E.H., A.J.B., A.J.W., A.M.W., K.N.E., L.M.M., and A.E.G. conducted experiments. O.E.H., A.L.E.-C., L.M.M., and P.T.E. analyzed the data. V.V. and J.T.S. provided key reagents. O.E.H. and S.L.O. wrote the manuscript. Funding Information: The Wisconsin National Primate Research Center is supported by grants P51RR000167 and P51OD011106. This study was funded through the National Institutes of Health (NIH R01 AI108415). Publisher Copyright: © 2022 American Society fo Microbiology. All Rights Reserved.

PY - 2022/12

Y1 - 2022/12

N2 - Vaccine strategies aimed at eliciting human immunodeficiency virus (HIV)-specific CD81 T cells are one major target of interest in HIV functional cure strategies. We hypothesized that CD81 T cells elicited by therapeutic vaccination during antiretroviral therapy (ART) would be recalled and boosted by treatment with the interleukin 15 (IL-15) superagonist N-803 after ART discontinuation. We intravenously immunized four simian immunodeficiency virus-positive (SIV1) Mauritian cynomolgus macaques receiving ART with vesicular stomatitis virus (VSV), modified vaccinia virus Ankara strain (MVA), and recombinant adenovirus serotype 5 (rAd-5) vectors all expressing SIVmac239 Gag. Immediately after ART cessation, these animals received three doses of N-803. Four control animals received no vaccines or N-803. The vaccine regimen generated a high-magnitude response involving Gag-specific CD81 T cells that were proliferative and biased toward an effector memory phenotype. We then compared cells elicited by vaccination (Gag specific) to cells elicited by SIV infection and unaffected by vaccination (Nef specific). We found that N-803 treatment enhanced the frequencies of both bulk and proliferating antigen-specific CD81 T cells elicited by vaccination and the antigen-specific CD81 T cells elicited by SIV infection. In sum, we demonstrate that a therapeutic heterologous prime-boost-boost (HPBB) vaccine can elicit antigen-specific effector memory CD81 T cells that are boosted by N-803.

AB - Vaccine strategies aimed at eliciting human immunodeficiency virus (HIV)-specific CD81 T cells are one major target of interest in HIV functional cure strategies. We hypothesized that CD81 T cells elicited by therapeutic vaccination during antiretroviral therapy (ART) would be recalled and boosted by treatment with the interleukin 15 (IL-15) superagonist N-803 after ART discontinuation. We intravenously immunized four simian immunodeficiency virus-positive (SIV1) Mauritian cynomolgus macaques receiving ART with vesicular stomatitis virus (VSV), modified vaccinia virus Ankara strain (MVA), and recombinant adenovirus serotype 5 (rAd-5) vectors all expressing SIVmac239 Gag. Immediately after ART cessation, these animals received three doses of N-803. Four control animals received no vaccines or N-803. The vaccine regimen generated a high-magnitude response involving Gag-specific CD81 T cells that were proliferative and biased toward an effector memory phenotype. We then compared cells elicited by vaccination (Gag specific) to cells elicited by SIV infection and unaffected by vaccination (Nef specific). We found that N-803 treatment enhanced the frequencies of both bulk and proliferating antigen-specific CD81 T cells elicited by vaccination and the antigen-specific CD81 T cells elicited by SIV infection. In sum, we demonstrate that a therapeutic heterologous prime-boost-boost (HPBB) vaccine can elicit antigen-specific effector memory CD81 T cells that are boosted by N-803.

KW - ART

KW - N-803

KW - SIV

KW - heterologous prime-boost-boost vaccination

KW - nonhuman primate

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DO - 10.1128/jvi.01424-22

M3 - Article

C2 - 36377872

AN - SCOPUS:85144585117

SN - 0022-538X

VL - 96

JO - Journal of virology

JF - Journal of virology

IS - 23

ER -

Transient T Cell Expansion, Activation, and Proliferation in Therapeutically Vaccinated Simian Immunodeficiency Virus-Positive Macaques Treated with N-803

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Keywords

UN SDGs

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