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^*

^*Corresponding author for this work

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

7 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
Externally published	Yes

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{f5a9740f16244946a26cc56b17e717a4,

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 = "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",

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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

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

Abstract

Keywords

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