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Small CD4 mimetics sensitize HIV-1-infected macrophages to antibody-dependent cellular cytotoxicity. 2023
Annemarie Laumaea, and
Lorie Marchitto, and
Shilei Ding, and
Guillaume Beaudoin-Bussières, and
Jérémie Prévost, and
Romain Gasser, and
Debashree Chatterjee, and
Gabrielle Gendron-Lepage, and
Halima Medjahed, and
Hung-Ching Chen, and
Amos B Smith, and
Haitao Ding, and
John C Kappes, and
Beatrice H Hahn, and
Frank Kirchhoff, and
Jonathan Richard, and
Ralf Duerr, and
Andrés Finzi
Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC H2X 0A9, Canada. Electronic address: annemarie.laumaea@umontreal.ca.
HIV-1 envelope (Env) conformation determines the susceptibility of infected CD4+ T cells to antibody-dependent cellular cytotoxicity (ADCC). Upon interaction with CD4, Env adopts more "open" conformations, exposing ADCC epitopes. HIV-1 limits Env-CD4 interaction and protects infected cells against ADCC by downregulating CD4 via Nef, Vpu, and Env. Limited data exist, however, of the role of these proteins in downmodulating CD4 on infected macrophages and how this impacts Env conformation. While Nef, Vpu, and Env are all required to efficiently downregulate CD4 on infected CD4+ T cells, we show here that any one of these proteins is sufficient to downmodulate most CD4 from the surface of infected macrophages. Consistent with this finding, Nef and Vpu have a lesser impact on Env conformation and ADCC sensitivity in infected macrophages compared with CD4+ T cells. However, treatment of infected macrophages with small CD4 mimetics exposes vulnerable CD4-induced Env epitopes and sensitizes them to ADCC.
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