HIV-1 Vpu restricts Fc-mediated effector functions in vivo

Jérémie Prévost; Sai Priya Anand; Jyothi Krishnaswamy Rajashekar; Li Zhu; Jonathan Richard; Guillaume Goyette; Halima Medjahed; Gabrielle Gendron-Lepage; Hung Ching Chen; Yaozong Chen; Joshua A. Horwitz; Michael W. Grunst; Susan Zolla-Pazner; Barton F. Haynes; Dennis R. Burton; Richard A. Flavell; Frank Kirchhoff; Beatrice H. Hahn; Amos B. Smith; Marzena Pazgier; Michel C. Nussenzweig; Priti Kumar; Andrés Finzi

doi:10.1016/j.celrep.2022.111624

HIV-1 Vpu restricts Fc-mediated effector functions in vivo

Jérémie Prévost, Sai Priya Anand, Jyothi Krishnaswamy Rajashekar, Li Zhu, Jonathan Richard, Guillaume Goyette, Halima Medjahed, Gabrielle Gendron-Lepage, Hung Ching Chen, Yaozong Chen, Joshua A. Horwitz, Michael W. Grunst, Susan Zolla-Pazner, Barton F. Haynes, Dennis R. Burton, Richard A. Flavell, Frank Kirchhoff, Beatrice H. Hahn, Amos B. Smith, Marzena PazgierMichel C. Nussenzweig, Priti Kumar, Andrés Finzi

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

2 Scopus citations

Abstract

Non-neutralizing antibodies (nnAbs) can eliminate HIV-1-infected cells via antibody-dependent cellular cytotoxicity (ADCC) and were identified as a correlate of protection in the RV144 vaccine trial. Fc-mediated effector functions of nnAbs were recently shown to alter the course of HIV-1 infection in vivo using a vpu-defective virus. Since Vpu is known to downregulate cell-surface CD4, which triggers conformational changes in the viral envelope glycoprotein (Env), we ask whether the lack of Vpu expression was linked to the observed nnAbs activity. We find that restoring Vpu expression greatly reduces nnAb recognition of infected cells, rendering them resistant to ADCC. Moreover, administration of nnAbs in humanized mice reduces viral loads only in animals infected with a vpu-defective but not with a wild-type virus. CD4-mimetics administration, known to “open” Env and expose nnAb epitopes, renders wild-type viruses sensitive to nnAbs Fc-effector functions. This work highlights the importance of Vpu-mediated evasion of humoral responses.

Original language	English
Article number	111624
Journal	Cell Reports
Volume	41
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2022.111624
State	Published - 8 Nov 2022

Keywords

ADCC
CD4 mimetics
CP: Immunology
Env
Fc-effector functions
HIV-1
Vpu
broadly neutralizing antibodies
humanized mice
immune evasion
non-neutralizing antibodies

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10.1016/j.celrep.2022.111624

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Prévost, J., Anand, S. P., Rajashekar, J. K., Zhu, L., Richard, J., Goyette, G., Medjahed, H., Gendron-Lepage, G., Chen, H. C., Chen, Y., Horwitz, J. A., Grunst, M. W., Zolla-Pazner, S., Haynes, B. F., Burton, D. R., Flavell, R. A., Kirchhoff, F., Hahn, B. H., Smith, A. B., ... Finzi, A. (2022). HIV-1 Vpu restricts Fc-mediated effector functions in vivo. Cell Reports, 41(6), Article 111624. https://doi.org/10.1016/j.celrep.2022.111624

@article{a4300e10fac84701902133e4b25b4f9e,

title = "HIV-1 Vpu restricts Fc-mediated effector functions in vivo",

abstract = "Non-neutralizing antibodies (nnAbs) can eliminate HIV-1-infected cells via antibody-dependent cellular cytotoxicity (ADCC) and were identified as a correlate of protection in the RV144 vaccine trial. Fc-mediated effector functions of nnAbs were recently shown to alter the course of HIV-1 infection in vivo using a vpu-defective virus. Since Vpu is known to downregulate cell-surface CD4, which triggers conformational changes in the viral envelope glycoprotein (Env), we ask whether the lack of Vpu expression was linked to the observed nnAbs activity. We find that restoring Vpu expression greatly reduces nnAb recognition of infected cells, rendering them resistant to ADCC. Moreover, administration of nnAbs in humanized mice reduces viral loads only in animals infected with a vpu-defective but not with a wild-type virus. CD4-mimetics administration, known to “open” Env and expose nnAb epitopes, renders wild-type viruses sensitive to nnAbs Fc-effector functions. This work highlights the importance of Vpu-mediated evasion of humoral responses.",

keywords = "ADCC, CD4 mimetics, CP: Immunology, Env, Fc-effector functions, HIV-1, Vpu, broadly neutralizing antibodies, humanized mice, immune evasion, non-neutralizing antibodies",

author = "J{\'e}r{\'e}mie Pr{\'e}vost and Anand, {Sai Priya} and Rajashekar, {Jyothi Krishnaswamy} and Li Zhu and Jonathan Richard and Guillaume Goyette and Halima Medjahed and Gabrielle Gendron-Lepage and Chen, {Hung Ching} and Yaozong Chen and Horwitz, {Joshua A.} and Grunst, {Michael W.} and Susan Zolla-Pazner and Haynes, {Barton F.} and Burton, {Dennis R.} and Flavell, {Richard A.} and Frank Kirchhoff and Hahn, {Beatrice H.} and Smith, {Amos B.} and Marzena Pazgier and Nussenzweig, {Michel C.} and Priti Kumar and Andr{\'e}s Finzi",

note = "Funding Information: The authors thank the CRCHUM BSL3 and flow cytometry platforms for technical assistance and Mario Legault from the Fonds de recherche du Qu{\'e}bec - Sant{\'e} (FRQS) AIDS and Infectious Diseases network for cohort coordination and clinical samples. We also thank David T. Evans (University of Wisconsin) for helpful discussions. We thank the following collaborators for kindly providing Abs: Julie Overbaugh (Fred Hutchinson Cancer Research Center) for QA255-006, QA255-067, and QA255-072; James Robinson (Tulane University) for 7B2, 2.2B, 12.3D, 12.4H, A32, C11, and 17b; George Lewis (University of Maryland) for M785U1, M785U2, M785U3, M785U4, N5U1, N5U2, N5U3, N10U1, and N10U2; Gunilla Karlsson Hedestam (Karolinska Institutet) for GE2-JG8; John Mascola (Vaccine Research Center, NIAID) for VRC01, VRC03, VRC07-523, VRC13, VRC16, and VRC34; Mark Connors (NIAID) for 10E8, N6, and 35O22; Florian Klein (University of Cologne) for 1–18; and the International AIDS Vaccine Initiative (IAVI) for PG9, PG16, PGT121, PGT122, PGT123, PGT125, PGT126, PGT128, PGT130, PGT135, PGT136, PGT145, and PGT151. We thank P. Mark Hogarth (Burnet Institute) for kindly providing recombinant dimeric FcγRIIIa. The graphical abstract and Figures 6 and 7 were prepared using illustrations from BioRender.com . This study was supported by a Canadian Institutes of Health Research ( CIHR ) foundation grant # 352417 to A.F. Funds were also provided by a CIHR team grant # 422148 to P.K. and A.F.; a Canada Foundation for Innovation ( CFI ) grant # 41027 to A.F.; and by the National Institutes of Health to A.F. ( R01 AI148379 and R01 AI150322 ), to M.P. and A.F. ( R01 AI129769 ), M.P. ( AI116274 ), and to P.K. ( R01 AI145164 , R33 AI122384 , and P50 AI150464 [CHEETAH]). Support for this work was also provided by P01 GM56550/AI150471 to A.B.S. and A.F. This work was partially supported by 1UM1AI164562-01 ; co-funded by National Heart, Lung, and Blood Institute ; National Institute of Diabetes and Digestive and Kidney Diseases ; National Institute of Neurological Disorders and Stroke ; National Institute on Drug Abuse , and the National Institute of Allergy and Infectious Diseases to A.F. A.F. is the recipient of a Canada Research Chair on Retroviral Entry # RCHS0235 950-232424 . F.K. is supported by the German Research Foundation ( DFG CRC 1279 and SPP1923 ) and the Baden-W{\"u}rttemberg Foundation ( BWST-ISF2018-032 ). J.P. and S.P.A. are recipients of CIHR doctoral fellowships. M.W.G. is a recipient of the Gruber Science Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The opinions and assertions expressed herein are those of the author(s) and do not necessarily reflect the official policy or position of the Uniformed Services University or the Department of Defense. Funding Information: The authors thank the CRCHUM BSL3 and flow cytometry platforms for technical assistance and Mario Legault from the Fonds de recherche du Qu{\'e}bec - Sant{\'e} (FRQS) AIDS and Infectious Diseases network for cohort coordination and clinical samples. We also thank David T. Evans (University of Wisconsin) for helpful discussions. We thank the following collaborators for kindly providing Abs: Julie Overbaugh (Fred Hutchinson Cancer Research Center) for QA255-006, QA255-067, and QA255-072; James Robinson (Tulane University) for 7B2, 2.2B, 12.3D, 12.4H, A32, C11, and 17b; George Lewis (University of Maryland) for M785U1, M785U2, M785U3, M785U4, N5U1, N5U2, N5U3, N10U1, and N10U2; Gunilla Karlsson Hedestam (Karolinska Institutet) for GE2-JG8; John Mascola (Vaccine Research Center, NIAID) for VRC01, VRC03, VRC07-523, VRC13, VRC16, and VRC34; Mark Connors (NIAID) for 10E8, N6, and 35O22; Florian Klein (University of Cologne) for 1–18; and the International AIDS Vaccine Initiative (IAVI) for PG9, PG16, PGT121, PGT122, PGT123, PGT125, PGT126, PGT128, PGT130, PGT135, PGT136, PGT145, and PGT151. We thank P. Mark Hogarth (Burnet Institute) for kindly providing recombinant dimeric FcγRIIIa. The graphical abstract and Figures 6 and 7 were prepared using illustrations from BioRender.com. This study was supported by a Canadian Institutes of Health Research (CIHR) foundation grant #352417 to A.F. Funds were also provided by a CIHR team grant #422148 to P.K. and A.F.; a Canada Foundation for Innovation (CFI) grant #41027 to A.F.; and by the National Institutes of Health to A.F. (R01 AI148379 and R01 AI150322), to M.P. and A.F. (R01 AI129769), M.P. (AI116274), and to P.K. (R01 AI145164, R33 AI122384, and P50 AI150464 [CHEETAH]). Support for this work was also provided by P01 GM56550/AI150471 to A.B.S. and A.F. This work was partially supported by 1UM1AI164562-01; co-funded by National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Neurological Disorders and Stroke; National Institute on Drug Abuse, and the National Institute of Allergy and Infectious Diseases to A.F. A.F. is the recipient of a Canada Research Chair on Retroviral Entry #RCHS0235 950-232424. F.K. is supported by the German Research Foundation (DFG CRC 1279 and SPP1923) and the Baden-W{\"u}rttemberg Foundation (BWST-ISF2018-032). J.P. and S.P.A. are recipients of CIHR doctoral fellowships. M.W.G. is a recipient of the Gruber Science Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The opinions and assertions expressed herein are those of the author(s) and do not necessarily reflect the official policy or position of the Uniformed Services University or the Department of Defense. Conceptualization, J.P. and A.F.; methodology: J.P. J.K.R. P.K. and A.F.; investigation, J.P. S.P.A. J.K.R. L.Z. J.R. G.G. H.M. G.G.-L. Y.C. and M.W.G.; resources, J.P. H.-C.C. J.A.H. S.Z.-P. B.F.H. D.R.B. R.A.F. F.K. B.H.H. A.B.S. M.P. M.C.N. P.K. and A.F.; formal analysis, J.P.; visualization, J.P.; supervision, A.B.S. M.P. M.C.N. P.K. and A.F.; funding acquisition, A.B.S. M.P. P.K. and A.F.; writing – original draft, J.P. B.H.H. and A.F.; writing – review & editing, all authors. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = nov,

day = "8",

doi = "10.1016/j.celrep.2022.111624",

language = "English",

volume = "41",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "6",

}

Prévost, J, Anand, SP, Rajashekar, JK, Zhu, L, Richard, J, Goyette, G, Medjahed, H, Gendron-Lepage, G, Chen, HC, Chen, Y, Horwitz, JA, Grunst, MW, Zolla-Pazner, S, Haynes, BF, Burton, DR, Flavell, RA, Kirchhoff, F, Hahn, BH, Smith, AB, Pazgier, M, Nussenzweig, MC, Kumar, P & Finzi, A 2022, 'HIV-1 Vpu restricts Fc-mediated effector functions in vivo', Cell Reports, vol. 41, no. 6, 111624. https://doi.org/10.1016/j.celrep.2022.111624

TY - JOUR

T1 - HIV-1 Vpu restricts Fc-mediated effector functions in vivo

AU - Prévost, Jérémie

AU - Anand, Sai Priya

AU - Rajashekar, Jyothi Krishnaswamy

AU - Zhu, Li

AU - Richard, Jonathan

AU - Goyette, Guillaume

AU - Medjahed, Halima

AU - Gendron-Lepage, Gabrielle

AU - Chen, Hung Ching

AU - Chen, Yaozong

AU - Horwitz, Joshua A.

AU - Grunst, Michael W.

AU - Zolla-Pazner, Susan

AU - Haynes, Barton F.

AU - Burton, Dennis R.

AU - Flavell, Richard A.

AU - Kirchhoff, Frank

AU - Hahn, Beatrice H.

AU - Smith, Amos B.

AU - Pazgier, Marzena

AU - Nussenzweig, Michel C.

AU - Kumar, Priti

AU - Finzi, Andrés

N1 - Funding Information: The authors thank the CRCHUM BSL3 and flow cytometry platforms for technical assistance and Mario Legault from the Fonds de recherche du Québec - Santé (FRQS) AIDS and Infectious Diseases network for cohort coordination and clinical samples. We also thank David T. Evans (University of Wisconsin) for helpful discussions. We thank the following collaborators for kindly providing Abs: Julie Overbaugh (Fred Hutchinson Cancer Research Center) for QA255-006, QA255-067, and QA255-072; James Robinson (Tulane University) for 7B2, 2.2B, 12.3D, 12.4H, A32, C11, and 17b; George Lewis (University of Maryland) for M785U1, M785U2, M785U3, M785U4, N5U1, N5U2, N5U3, N10U1, and N10U2; Gunilla Karlsson Hedestam (Karolinska Institutet) for GE2-JG8; John Mascola (Vaccine Research Center, NIAID) for VRC01, VRC03, VRC07-523, VRC13, VRC16, and VRC34; Mark Connors (NIAID) for 10E8, N6, and 35O22; Florian Klein (University of Cologne) for 1–18; and the International AIDS Vaccine Initiative (IAVI) for PG9, PG16, PGT121, PGT122, PGT123, PGT125, PGT126, PGT128, PGT130, PGT135, PGT136, PGT145, and PGT151. We thank P. Mark Hogarth (Burnet Institute) for kindly providing recombinant dimeric FcγRIIIa. The graphical abstract and Figures 6 and 7 were prepared using illustrations from BioRender.com . This study was supported by a Canadian Institutes of Health Research ( CIHR ) foundation grant # 352417 to A.F. Funds were also provided by a CIHR team grant # 422148 to P.K. and A.F.; a Canada Foundation for Innovation ( CFI ) grant # 41027 to A.F.; and by the National Institutes of Health to A.F. ( R01 AI148379 and R01 AI150322 ), to M.P. and A.F. ( R01 AI129769 ), M.P. ( AI116274 ), and to P.K. ( R01 AI145164 , R33 AI122384 , and P50 AI150464 [CHEETAH]). Support for this work was also provided by P01 GM56550/AI150471 to A.B.S. and A.F. This work was partially supported by 1UM1AI164562-01 ; co-funded by National Heart, Lung, and Blood Institute ; National Institute of Diabetes and Digestive and Kidney Diseases ; National Institute of Neurological Disorders and Stroke ; National Institute on Drug Abuse , and the National Institute of Allergy and Infectious Diseases to A.F. A.F. is the recipient of a Canada Research Chair on Retroviral Entry # RCHS0235 950-232424 . F.K. is supported by the German Research Foundation ( DFG CRC 1279 and SPP1923 ) and the Baden-Württemberg Foundation ( BWST-ISF2018-032 ). J.P. and S.P.A. are recipients of CIHR doctoral fellowships. M.W.G. is a recipient of the Gruber Science Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The opinions and assertions expressed herein are those of the author(s) and do not necessarily reflect the official policy or position of the Uniformed Services University or the Department of Defense. Funding Information: The authors thank the CRCHUM BSL3 and flow cytometry platforms for technical assistance and Mario Legault from the Fonds de recherche du Québec - Santé (FRQS) AIDS and Infectious Diseases network for cohort coordination and clinical samples. We also thank David T. Evans (University of Wisconsin) for helpful discussions. We thank the following collaborators for kindly providing Abs: Julie Overbaugh (Fred Hutchinson Cancer Research Center) for QA255-006, QA255-067, and QA255-072; James Robinson (Tulane University) for 7B2, 2.2B, 12.3D, 12.4H, A32, C11, and 17b; George Lewis (University of Maryland) for M785U1, M785U2, M785U3, M785U4, N5U1, N5U2, N5U3, N10U1, and N10U2; Gunilla Karlsson Hedestam (Karolinska Institutet) for GE2-JG8; John Mascola (Vaccine Research Center, NIAID) for VRC01, VRC03, VRC07-523, VRC13, VRC16, and VRC34; Mark Connors (NIAID) for 10E8, N6, and 35O22; Florian Klein (University of Cologne) for 1–18; and the International AIDS Vaccine Initiative (IAVI) for PG9, PG16, PGT121, PGT122, PGT123, PGT125, PGT126, PGT128, PGT130, PGT135, PGT136, PGT145, and PGT151. We thank P. Mark Hogarth (Burnet Institute) for kindly providing recombinant dimeric FcγRIIIa. The graphical abstract and Figures 6 and 7 were prepared using illustrations from BioRender.com. This study was supported by a Canadian Institutes of Health Research (CIHR) foundation grant #352417 to A.F. Funds were also provided by a CIHR team grant #422148 to P.K. and A.F.; a Canada Foundation for Innovation (CFI) grant #41027 to A.F.; and by the National Institutes of Health to A.F. (R01 AI148379 and R01 AI150322), to M.P. and A.F. (R01 AI129769), M.P. (AI116274), and to P.K. (R01 AI145164, R33 AI122384, and P50 AI150464 [CHEETAH]). Support for this work was also provided by P01 GM56550/AI150471 to A.B.S. and A.F. This work was partially supported by 1UM1AI164562-01; co-funded by National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Neurological Disorders and Stroke; National Institute on Drug Abuse, and the National Institute of Allergy and Infectious Diseases to A.F. A.F. is the recipient of a Canada Research Chair on Retroviral Entry #RCHS0235 950-232424. F.K. is supported by the German Research Foundation (DFG CRC 1279 and SPP1923) and the Baden-Württemberg Foundation (BWST-ISF2018-032). J.P. and S.P.A. are recipients of CIHR doctoral fellowships. M.W.G. is a recipient of the Gruber Science Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The opinions and assertions expressed herein are those of the author(s) and do not necessarily reflect the official policy or position of the Uniformed Services University or the Department of Defense. Conceptualization, J.P. and A.F.; methodology: J.P. J.K.R. P.K. and A.F.; investigation, J.P. S.P.A. J.K.R. L.Z. J.R. G.G. H.M. G.G.-L. Y.C. and M.W.G.; resources, J.P. H.-C.C. J.A.H. S.Z.-P. B.F.H. D.R.B. R.A.F. F.K. B.H.H. A.B.S. M.P. M.C.N. P.K. and A.F.; formal analysis, J.P.; visualization, J.P.; supervision, A.B.S. M.P. M.C.N. P.K. and A.F.; funding acquisition, A.B.S. M.P. P.K. and A.F.; writing – original draft, J.P. B.H.H. and A.F.; writing – review & editing, all authors. The authors declare no competing interests. Publisher Copyright: © 2022 The Authors

PY - 2022/11/8

Y1 - 2022/11/8

N2 - Non-neutralizing antibodies (nnAbs) can eliminate HIV-1-infected cells via antibody-dependent cellular cytotoxicity (ADCC) and were identified as a correlate of protection in the RV144 vaccine trial. Fc-mediated effector functions of nnAbs were recently shown to alter the course of HIV-1 infection in vivo using a vpu-defective virus. Since Vpu is known to downregulate cell-surface CD4, which triggers conformational changes in the viral envelope glycoprotein (Env), we ask whether the lack of Vpu expression was linked to the observed nnAbs activity. We find that restoring Vpu expression greatly reduces nnAb recognition of infected cells, rendering them resistant to ADCC. Moreover, administration of nnAbs in humanized mice reduces viral loads only in animals infected with a vpu-defective but not with a wild-type virus. CD4-mimetics administration, known to “open” Env and expose nnAb epitopes, renders wild-type viruses sensitive to nnAbs Fc-effector functions. This work highlights the importance of Vpu-mediated evasion of humoral responses.

AB - Non-neutralizing antibodies (nnAbs) can eliminate HIV-1-infected cells via antibody-dependent cellular cytotoxicity (ADCC) and were identified as a correlate of protection in the RV144 vaccine trial. Fc-mediated effector functions of nnAbs were recently shown to alter the course of HIV-1 infection in vivo using a vpu-defective virus. Since Vpu is known to downregulate cell-surface CD4, which triggers conformational changes in the viral envelope glycoprotein (Env), we ask whether the lack of Vpu expression was linked to the observed nnAbs activity. We find that restoring Vpu expression greatly reduces nnAb recognition of infected cells, rendering them resistant to ADCC. Moreover, administration of nnAbs in humanized mice reduces viral loads only in animals infected with a vpu-defective but not with a wild-type virus. CD4-mimetics administration, known to “open” Env and expose nnAb epitopes, renders wild-type viruses sensitive to nnAbs Fc-effector functions. This work highlights the importance of Vpu-mediated evasion of humoral responses.

KW - ADCC

KW - CD4 mimetics

KW - CP: Immunology

KW - Env

KW - Fc-effector functions

KW - HIV-1

KW - Vpu

KW - broadly neutralizing antibodies

KW - humanized mice

KW - immune evasion

KW - non-neutralizing antibodies

UR - http://www.scopus.com/inward/record.url?scp=85141505207&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2022.111624

DO - 10.1016/j.celrep.2022.111624

M3 - Article

C2 - 36351384

AN - SCOPUS:85141505207

SN - 2211-1247

VL - 41

JO - Cell Reports

JF - Cell Reports

IS - 6

M1 - 111624

ER -

HIV-1 Vpu restricts Fc-mediated effector functions in vivo

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