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

• Published in: Cell host & microbe 2021-06, Vol.29 (6), p.904-916.e6
• Main Authors: Rajashekar, Jyothi K., Richard, Jonathan, Beloor, Jagadish, Prévost, Jérémie, Anand, Sai Priya, Beaudoin-Bussières, Guillaume, Shan, Liang, Herndler-Brandstetter, Dietmar, Gendron-Lepage, Gabrielle, Medjahed, Halima, Bourassa, Catherine, Gaudette, Fleur, Ullah, Irfan, Symmes, Kelly, Peric, Andrew, Lindemuth, Emily, Bibollet-Ruche, Frederic, Park, Jun, Chen, Hung-Ching, Kaufmann, Daniel E., Hahn, Beatrice H., Sodroski, Joseph, Pazgier, Marzena, Flavell, Richard A., Smith, Amos B., Finzi, Andrés, Kumar, Priti
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Neutralizing - immunology; Antibodies, Neutralizing - therapeutic use; Antibody-Dependent Cell Cytotoxicity; antibody-dependent cellular cytotoxicity; Antiviral Agents - therapeutic use; CD4 Antigens - chemistry; CD4 Antigens - metabolism; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - virology; CD4i Abs; Cell Line; env Gene Products, Human Immunodeficiency Virus - chemistry; env Gene Products, Human Immunodeficiency Virus - immunology; envelope glycoprotein; Epitopes - immunology; Female; Glycoproteins - chemistry; Glycoproteins - immunology; HEK293 Cells; HIV Infections - drug therapy; HIV Infections - immunology; HIV Infections - virology; HIV-1; HIV-1 - chemistry; HIV-1 - drug effects; HIV-1 - immunology; humanized mice; Humans; Immunoglobulin Fc Fragments - immunology; Killer Cells, Natural - immunology; Male; Mice; Mice, SCID; Models, Animal; NK cell; Protein Conformation; SRG-15; State 2A; Virus Replication - drug effects
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2021.04.014

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. [Display omitted] •CD4mc with CD4-induced Abs decrease the HIV-1 reservoir in SRG15-hu-mice•This treatment significantly delays viral rebound after ART interruption•This approach is dependent on Fc-effector function•CD4mc and HIV+ donor plasma suppress rebound in patient-cell-derived hu-mice Rajashekar et al. show that a small molecule CD4 mimetic, in concert with non-neutralizing antibodies, decreases the size of HIV-1 reservoir in new generation humanized mice supporting antibody and NK cell functions. Since these non-neutralizing antibodies exist in most HIV-1-infected individuals, CD4mc could translate to a functional cure strategy for HIV-AIDS.