| Literature DB >> 30974085 |
Nirmin Alsahafi1, Nordine Bakouche2, Mohsen Kazemi3, Jonathan Richard4, Shilei Ding4, Sudipta Bhattacharyya3, Durba Das3, Sai Priya Anand1, Jérémie Prévost4, William D Tolbert5, Hong Lu6, Halima Medjahed7, Gabrielle Gendron-Lepage7, Gloria Gabrielle Ortega Delgado7, Sharon Kirk8, Bruno Melillo8, Walther Mothes9, Joseph Sodroski10, Amos B Smith8, Daniel E Kaufmann11, Xueling Wu6, Marzena Pazgier5, Isabelle Rouiller12, Andrés Finzi13, James B Munro14.
Abstract
The HIV-1 envelope glycoprotein (Env) (gp120-gp41)3 is the target for neutralizing antibodies and antibody-dependent cellular cytotoxicity (ADCC). HIV-1 Env is flexible, sampling different conformational states. Before engaging CD4, Env adopts a closed conformation (State 1) that is largely antibody resistant. CD4 binding induces an intermediate state (State 2), followed by an open conformation (State 3) that is susceptible to engagement by antibodies that recognize otherwise occluded epitopes. We investigate conformational changes in Env that induce ADCC in the presence of a small-molecule CD4-mimetic compound (CD4mc). We uncover an asymmetric Env conformation (State 2A) recognized by antibodies targeting the conserved gp120 inner domain and mediating ADCC. Sera from HIV+ individuals contain these antibodies, which can stabilize Env State 2A in combination with CD4mc. Additionally, triggering State 2A on HIV-infected primary CD4+ T cells exposes epitopes that induce ADCC. Strategies that induce this Env conformation may represent approaches to fight HIV-1 infection.Entities:
Keywords: 17b; A32; ADCC; CD4i Abs; HIV-1; State 2A; cryo-EM; envelope glycoproteins; smFRET
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Year: 2019 PMID： 30974085 PMCID： PMC6592637 DOI： 10.1016/j.chom.2019.03.002
Source DB: PubMed Journal: Cell Host Microbe ISSN： 1931-3128 Impact factor: 21.023