Cocrystal structures of antibody N60-i3 and antibody JR4 in complex with gp120 define more cluster A epitopes involved in effective antibody-dependent effector function against HIV-1

Neelakshi Gohain, William D. Tolbert, Priyamvada Acharya, Lei Yu, Tongyun Liu, Pingsen Zhao, Chiara Orlandi, Maria L. Visciano, Roberta Kamin-Lewis, Mohammad M. Sajadi, Loïc Martin, James E. Robinson, Peter D. Kwong, Anthony L. DeVico, Krishanu Ray, George K. Lewis, Marzena Pazgier*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Accumulating evidence indicates a role for Fc receptor (FcR)-mediated effector functions of antibodies, including antibody-dependent cell-mediated cytotoxicity (ADCC), in prevention of human immunodeficiency virus type 1 (HIV-1) acquisition and in postinfection control of viremia. Consequently, an understanding of the molecular basis for Env epitopes that constitute effective ADCC targets is of fundamental interest for humoral anti-HIV-1 immunity and for HIV-1 vaccine design. A substantial portion of FcR effector function of potentially protective anti-HIV-1 antibodies is directed toward nonneutralizing, transitional, CD4-inducible (CD4i) epitopes associated with the gp41-reactive region of gp120 (cluster A epitopes). Our previous studies defined the A32-like epitope within the cluster A region and mapped it to the highly conserved and mobile layers 1 and 2 of the gp120 inner domain within the C1-C2 regions of gp120. Here, we elucidate additional cluster A epitope structures, including an A32-like epitope, recognized by human monoclonal antibody (MAb) N60-i3, and a hybrid A32-C11-like epitope, recognized by rhesus macaque MAb JR4. These studies define for the first time a hybrid A32-C11-like epitope and map it to elements of both the A32-like subregion and the seven-layered β-sheet of the gp41-interactive region of gp120. These studies provide additional evidence that effective antibody-dependent effector function in the cluster A region depends on precise epitope targeting-a combination of epitope footprint and mode of antibody attachment. All together these findings help further an understanding of how cluster A epitopes are targeted by humoral responses.

Original languageEnglish
Pages (from-to)8840-8854
Number of pages15
JournalJournal of Virology
Volume89
Issue number17
DOIs
StatePublished - 2015
Externally publishedYes

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