Interaction with Cellular CD4 Exposes HIV-1 Envelope Epitopes Targeted by Antibody-Dependent Cell-Mediated Cytotoxicity

• DOI: 10.1128/jvi.03230-13
• Publication Date: 2013-12-19T07:25:34Z
• Authors: Maxime Veillette; Anik Désormeaux; Halima Medjahed; Nour-Elhouda Ghar...; Mathieu Coutu; Joshua Baalwa; Yongjun Guan; George Lewis; Guido Ferrari; Beatrice H. Hahn; Barton F. Haynes; James E. Robinson; Daniel E. Kaufmann; Mattia Bonsignori; Joseph Sodroski; Andrés Finzi
• Keywords: CD4-Positive T-Lymphocytes; Models, Molecular; 0301 basic medicine; Protein Conformation; Human Immunodeficiency Virus Proteins; Antibody-Dependent Cell Cytotoxicity; env Gene Products, Human Immunodeficiency Virus; Epitopes, T-Lymphocyte; HIV Infections; HIV Antibodies; Cell Line; 3. Good health; 03 medical and health sciences; CD4 Antigens; HIV-1; Humans; Protein Interaction Domains and Motifs; Viral Regulatory and Accessory Proteins; nef Gene Products, Human Immunodeficiency Virus; Protein Multimerization; Protein Binding

Anti-HIV-1 envelope glycoprotein (Env) antibodies without broadly neutralizing activity correlated with protection in the RV144 clinical trial, stimulating interest other protective mechanisms involving antibodies, such as antibody-dependent cell-mediated cytotoxicity (ADCC). Env epitopes targeted by many effective at mediating ADCC are poorly exposed on unliganded trimer. Here we investigated mechanism of exposure and showed that binding CD4 within same HIV-1-infected cell effectively exposes these epitopes. capacity to transit CD4-bound conformation is required for epitope exposure. Importantly, surface downregulation Nef Vpu accessory proteins Vpu-mediated BST-2 antagonism modulate ADCC-mediating reduce susceptibility infected cells this effector function vitro. Significantly, conformational changes induced conserved among from HIV-1 HIV-2/SIVmac lineages. Altogether, our observations describe a highly expose might help explain evolutionary advantage proteins.HIV-1 (ADCC) found interaction receptor some Moreover, results suggest avoid killing immune mechanism.