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

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.; Kaufmann, D.E.; Hahn, B.H.; Sodroski, J.; Pazgier, M.; Flavell, R.A.; Smith, A.B.; Finzi, A.; Kumar, P.

doi:10.1016/j.chom.2021.04.014

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

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Serval ID

serval:BIB_047E6CF6A88E

Type

Article: article from journal or magazin.

Collection

Publications

Institution

Production externe

Title

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

Journal

Cell host & microbe

Author(s)

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., Kaufmann D.E., Hahn B.H., Sodroski J., Pazgier M., Flavell R.A., Smith A.B., Finzi A., Kumar P.

ISSN

1934-6069 (Electronic)

ISSN-L

1931-3128

Publication state

Published

Issued date

09/06/2021

Peer-reviewed

Oui

Volume

Number

Pages

904-916.e6

Language

english

Notes

Publication types: Journal Article
Publication Status: ppublish

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.

Keywords

Animals, Antibodies, Neutralizing/immunology, Antibodies, Neutralizing/therapeutic use, Antibody-Dependent Cell Cytotoxicity, Antiviral Agents/therapeutic use, CD4 Antigens/chemistry, CD4 Antigens/metabolism, CD4-Positive T-Lymphocytes/immunology, CD4-Positive T-Lymphocytes/virology, Cell Line, Epitopes/immunology, Female, Glycoproteins/chemistry, Glycoproteins/immunology, HEK293 Cells, HIV Infections/drug therapy, HIV Infections/immunology, HIV Infections/virology, HIV-1/chemistry, HIV-1/drug effects, HIV-1/immunology, Humans, Immunoglobulin Fc Fragments/immunology, Killer Cells, Natural/immunology, Male, Mice, Mice, SCID, Models, Animal, Protein Conformation, Virus Replication/drug effects, env Gene Products, Human Immunodeficiency Virus/chemistry, env Gene Products, Human Immunodeficiency Virus/immunology, CD4i Abs, HIV-1, NK cell, SRG-15, State 2A, antibody-dependent cellular cytotoxicity, envelope glycoprotein, humanized mice

DOI

10.1016/j.chom.2021.04.014

Pubmed

34019804

Web of science

000661313200010

Publisher's website

http://europepmc.org/abstract/med/34019804

Open Access

Yes

Create date

09/05/2023 12:59