Defining rules governing recognition and Fc-mediated effector functions to the HIV-1 co-receptor binding site

作者：William D. Tolbert, Rebekah Sherburn, Neelakshi Gohain, Shilei Ding, Robin Flinko, Chiara Orlandi, Krishanu Ray, Andrés Finzi, George K. Lewis, Marzena Pazgier · 发表于：BMC Biology · 年份：2020 · DOI：10.1186/s12915-020-00819-y · 被引用次数：28 · 研究领域：HIV Research and Treatment、Chemokine receptors and signaling、Monoclonal and Polyclonal Antibodies Research

BACKGROUND: The binding of HIV-1 Envelope glycoproteins (Env) to host receptor CD4 exposes vulnerable conserved epitopes within the co-receptor binding site (CoRBS) which are required for the engagement of either CCR5 or CXCR4 co-receptor to allow HIV-1 entry. Antibodies against this region have been implicated in the protection against HIV acquisition in non-human primate (NHP) challenge studies and found to act synergistically with antibodies of other specificities to deliver effective Fc-mediated effector function against HIV-1-infected cells. Here, we describe the structure and function of N12-i2, an antibody isolated from an HIV-1-infected individual, and show how the unique structural features of this antibody allow for its effective Env recognition and Fc-mediated effector function. RESULTS: N12-i2 binds within the CoRBS utilizing two adjacent sulfo-tyrosines (TYS) for binding, one of which binds to a previously unknown TYS binding pocket formed by gp120 residues of high sequence conservation among HIV-1 strains. Structural alignment with gp120 in complex with the co-receptor CCR5 indicates that the new pocket corresponds to TYS at position 15 of CCR5. In addition, structure-function analysis of N12-i2 and other CoRBS-specific antibodies indicates a link between modes of antibody binding within the CoRBS and Fc-mediated effector activities. The efficiency of antibody-dependent cellular cytotoxicity (ADCC) correlated with both the level of antibody binding and the mode ...