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C-105 Quaternary Configuration of the HIV-1 Receptor-Binding Site

Lusso, Paulo, MD, PhD*; Liu, Qingbo, PhD; Acharya, Priyamvada, PhD; Dolan, Michael, PhD; Zhang, Peng, PhD; Guzzo, Christina, PhD; Lu, Jacky, MS; Kwon, Alice, MS; Gururani, Deepali, MS

JAIDS Journal of Acquired Immune Deficiency Syndromes: April 2018 - Volume 77 - Issue - p 38
doi: 10.1097/01.qai.0000532592.74801.1a
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The native trimeric HIV-1 envelope (Env) spike displayed on the surface of mature virions is the sole functional form that mediates viral attachment and entry. Interaction of conserved elements in the external envelope glycoprotein, gp120, with the CD4 receptor is the first critical step in the HIV-1 infectious cycle. Although the CD4-binding site in gp120 has been extensively characterized by mutagenesis and co-crystallization with soluble CD4, most of these studies were performed on monomeric gp120 subunits, precluding the recognition of potential quaternary-specific components. Here, we show that the functional HIV-1 Env trimer interacts with CD4 through a quaternary surface formed by coalescence of the previously defined CD4-contact region in the gp120 outer domain with a second binding site (CD4-BS2) in the inner domain of a neighboring gp120 protomer. Disruption of CD4-BS2 in diverse HIV-1 Envs reduces the stability of CD4-trimer interaction and abrogates HIV-1 infectivity by preventing the acquisition of coreceptor-binding competence. A corresponding reduction in HIV-1 infectivity occurs upon mutation of CD4 residues that interact with CD4-BS2. A 6.8-Å cryoEM structure of a stabilized trimer (DS-SOSIP) in complex with soluble CD4 confirmed the quaternary contact. Selected neutralizing human antibodies also recognize a quaternary surface that spans CD4-BS2, providing evidence that this region is immunogenic in vivo. These results document the quaternary configuration of the functional HIV-1 receptor-binding site, with implications for treatment and vaccine design.

*National Institute of Allergy and Infectious Diseases

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