Modulating HIV-1 envelope glycoprotein conformation to decrease the HIV-1 reservoir

Jyothi K. Rajashekar; Jonathan Richard; Jagadish Beloor; Jérémie Prévost; Sai Priya Anand; Guillaume Beaudoin-Bussières; Liang Shan; Dietmar Herndler-Brandstetter; Gabrielle Gendron-Lepage; Halima Medjahed; Catherine Bourassa; Fleur Gaudette; Irfan Ullah; Kelly Symmes; Andrew Peric; Emily Lindemuth; Frederic Bibollet-Ruche; Jun Park; Hung Ching Chen; Daniel E. Kaufmann; Beatrice H. Hahn; Joseph Sodroski; Marzena Pazgier; Richard A. Flavell; Amos B. Smith; Andrés Finzi; Priti Kumar

doi:10.1016/j.chom.2021.04.014

Modulating HIV-1 envelope glycoprotein conformation to decrease the HIV-1 reservoir

Jyothi K. Rajashekar
, Jonathan Richard
, Jagadish Beloor
, Jérémie Prévost
, Sai Priya Anand
, Guillaume Beaudoin-Bussières
, Liang Shan
, Dietmar Herndler-Brandstetter
, Gabrielle Gendron-Lepage
, Halima Medjahed
, Catherine Bourassa
, Fleur Gaudette
, Irfan Ullah
, Kelly Symmes
, Andrew Peric
, Emily Lindemuth
, Frederic Bibollet-Ruche
, Jun Park
, Hung Ching Chen
, Daniel E. Kaufmann

Beatrice H. Hahn, Joseph Sodroski, Marzena Pazgier, Richard A. Flavell^*, Amos B. Smith^*, Andrés Finzi^*, Priti Kumar^*

^*Corresponding author for this work

Medicine

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

38 Scopus citations

Abstract

Small CD4-mimetic compounds (CD4mc) sensitize HIV-1-infected cells to antibody-dependent cellular cytotoxicity (ADCC) by facilitating antibody recognition of epitopes that are otherwise occluded on the unliganded viral envelope (Env). Combining CD4mc with two families of CD4-induced (CD4i) antibodies, which are frequently found in plasma of HIV-1-infected individuals, stabilizes Env in a conformation that is vulnerable to ADCC. We employed new-generation SRG-15 humanized mice, supporting natural killer (NK) cell and Fc-effector functions to demonstrate that brief treatment with CD4mc and CD4i-Abs significantly decreases HIV-1 replication, the virus reservoir and viral rebound after ART interruption. These effects required Fc-effector functions and NK cells, highlighting the importance of ADCC. Viral rebound was also suppressed in HIV-1+-donor cell-derived humanized mice supplemented with autologous HIV-1+-donor-derived plasma and CD4mc. These results indicate that CD4mc could have therapeutic utility in infected individuals for decreasing the size of the HIV-1 reservoir and/or achieving a functional cure.

Original language	English
Pages (from-to)	904-916.e6
Journal	Cell Host and Microbe
Volume	29
Issue number	6
DOIs	https://doi.org/10.1016/j.chom.2021.04.014
State	Published - 9 Jun 2021

Keywords

CD4i Abs
HIV-1
NK cell
SRG-15
State 2A
antibody-dependent cellular cytotoxicity
envelope glycoprotein
humanized mice

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10.1016/j.chom.2021.04.014

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Rajashekar, J. K., Richard, J., Beloor, J., Prévost, J., Anand, S. P., Beaudoin-Bussières, G., Shan, L., Herndler-Brandstetter, D., Gendron-Lepage, G., Medjahed, H., Bourassa, C., Gaudette, F., Ullah, I., Symmes, K., Peric, A., Lindemuth, E., Bibollet-Ruche, F., Park, J., Chen, H. C., ... Kumar, P. (2021). Modulating HIV-1 envelope glycoprotein conformation to decrease the HIV-1 reservoir. Cell Host and Microbe, 29(6), 904-916.e6. https://doi.org/10.1016/j.chom.2021.04.014

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title = "Modulating HIV-1 envelope glycoprotein conformation to decrease the HIV-1 reservoir",

abstract = "Small CD4-mimetic compounds (CD4mc) sensitize HIV-1-infected cells to antibody-dependent cellular cytotoxicity (ADCC) by facilitating antibody recognition of epitopes that are otherwise occluded on the unliganded viral envelope (Env). Combining CD4mc with two families of CD4-induced (CD4i) antibodies, which are frequently found in plasma of HIV-1-infected individuals, stabilizes Env in a conformation that is vulnerable to ADCC. We employed new-generation SRG-15 humanized mice, supporting natural killer (NK) cell and Fc-effector functions to demonstrate that brief treatment with CD4mc and CD4i-Abs significantly decreases HIV-1 replication, the virus reservoir and viral rebound after ART interruption. These effects required Fc-effector functions and NK cells, highlighting the importance of ADCC. Viral rebound was also suppressed in HIV-1+-donor cell-derived humanized mice supplemented with autologous HIV-1+-donor-derived plasma and CD4mc. These results indicate that CD4mc could have therapeutic utility in infected individuals for decreasing the size of the HIV-1 reservoir and/or achieving a functional cure.",

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doi = "10.1016/j.chom.2021.04.014",

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Rajashekar, JK, Richard, J, Beloor, J, Prévost, J, Anand, SP, Beaudoin-Bussières, G, Shan, L, Herndler-Brandstetter, D, Gendron-Lepage, G, Medjahed, H, Bourassa, C, Gaudette, F, Ullah, I, Symmes, K, Peric, A, Lindemuth, E, Bibollet-Ruche, F, Park, J, Chen, HC, Kaufmann, DE, Hahn, BH, Sodroski, J, Pazgier, M, Flavell, RA, Smith, AB, Finzi, A & Kumar, P 2021, 'Modulating HIV-1 envelope glycoprotein conformation to decrease the HIV-1 reservoir', Cell Host and Microbe, vol. 29, no. 6, pp. 904-916.e6. https://doi.org/10.1016/j.chom.2021.04.014

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AU - Rajashekar, Jyothi K.

AU - Richard, Jonathan

AU - Beloor, Jagadish

AU - Prévost, Jérémie

AU - Anand, Sai Priya

AU - Beaudoin-Bussières, Guillaume

AU - Shan, Liang

AU - Herndler-Brandstetter, Dietmar

AU - Gendron-Lepage, Gabrielle

AU - Medjahed, Halima

AU - Bourassa, Catherine

AU - Gaudette, Fleur

AU - Ullah, Irfan

AU - Symmes, Kelly

AU - Peric, Andrew

AU - Lindemuth, Emily

AU - Bibollet-Ruche, Frederic

AU - Park, Jun

AU - Chen, Hung Ching

AU - Kaufmann, Daniel E.

AU - Hahn, Beatrice H.

AU - Sodroski, Joseph

AU - Pazgier, Marzena

AU - Flavell, Richard A.

AU - Smith, Amos B.

AU - Finzi, Andrés

AU - Kumar, Priti

PY - 2021/6/9

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N2 - Small CD4-mimetic compounds (CD4mc) sensitize HIV-1-infected cells to antibody-dependent cellular cytotoxicity (ADCC) by facilitating antibody recognition of epitopes that are otherwise occluded on the unliganded viral envelope (Env). Combining CD4mc with two families of CD4-induced (CD4i) antibodies, which are frequently found in plasma of HIV-1-infected individuals, stabilizes Env in a conformation that is vulnerable to ADCC. We employed new-generation SRG-15 humanized mice, supporting natural killer (NK) cell and Fc-effector functions to demonstrate that brief treatment with CD4mc and CD4i-Abs significantly decreases HIV-1 replication, the virus reservoir and viral rebound after ART interruption. These effects required Fc-effector functions and NK cells, highlighting the importance of ADCC. Viral rebound was also suppressed in HIV-1+-donor cell-derived humanized mice supplemented with autologous HIV-1+-donor-derived plasma and CD4mc. These results indicate that CD4mc could have therapeutic utility in infected individuals for decreasing the size of the HIV-1 reservoir and/or achieving a functional cure.

AB - Small CD4-mimetic compounds (CD4mc) sensitize HIV-1-infected cells to antibody-dependent cellular cytotoxicity (ADCC) by facilitating antibody recognition of epitopes that are otherwise occluded on the unliganded viral envelope (Env). Combining CD4mc with two families of CD4-induced (CD4i) antibodies, which are frequently found in plasma of HIV-1-infected individuals, stabilizes Env in a conformation that is vulnerable to ADCC. We employed new-generation SRG-15 humanized mice, supporting natural killer (NK) cell and Fc-effector functions to demonstrate that brief treatment with CD4mc and CD4i-Abs significantly decreases HIV-1 replication, the virus reservoir and viral rebound after ART interruption. These effects required Fc-effector functions and NK cells, highlighting the importance of ADCC. Viral rebound was also suppressed in HIV-1+-donor cell-derived humanized mice supplemented with autologous HIV-1+-donor-derived plasma and CD4mc. These results indicate that CD4mc could have therapeutic utility in infected individuals for decreasing the size of the HIV-1 reservoir and/or achieving a functional cure.

KW - CD4i Abs

KW - HIV-1

KW - NK cell

KW - SRG-15

KW - State 2A

KW - antibody-dependent cellular cytotoxicity

KW - envelope glycoprotein

KW - humanized mice

UR - https://www.scopus.com/pages/publications/85108124159

U2 - 10.1016/j.chom.2021.04.014

DO - 10.1016/j.chom.2021.04.014

M3 - Article

C2 - 34019804

AN - SCOPUS:85108124159

SN - 1931-3128

VL - 29

SP - 904-916.e6

JO - Cell Host and Microbe

JF - Cell Host and Microbe

IS - 6

ER -

Modulating HIV-1 envelope glycoprotein conformation to decrease the HIV-1 reservoir

Abstract

Keywords

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