Molecular basis for epitope recognition by non-neutralizing anti-gp41 antibody F240.

Neelakshi Gohain,Jonathan Richard,William D Tolbert,Wuyuan Lu,Chiara Orlandi,Xishan Chen,Marzena Pazgier,Andrés Finzi,Daniel A Bonsor,Eric J Sundberg,Krishanu Ray,George K Lewis,Shilei Ding

doi:10.1038/srep36685

Abstract

Antibody-dependent cell-mediated cytotoxicity (ADCC) by non-neutralizing antibodies (nnAbs) specific to the HIV envelope (Env) glycoproteins present at the surface of virus sensitized or infected cells plays a role in the effective adaptive immune response to HIV. Here, we explore the molecular basis for the epitope at the disulfide loop region (DLR) of the principal immunodominant domain of gp41, recognized by the well-known nnAb F240. Our structural studies reveal details of the F240-gp41 interface and describe a structure of DLR that is distinct from known conformations of this region studied in the context of either CD4-unliganded Env trimer or the gp41 peptide in the unbound state. These data coupled with binding and functional analyses indicate that F240 recognizes non-trimeric Env forms which are significantly overexpressed on intact virions but poorly represented at surfaces of cells infected with infectious molecular clones and endogenously-infected CD4 T cells from HIV-1-infected individuals. Furthermore, although we detect ADCC activities of F240 against cells spinoculated with intact virions, our data suggest that these activities result from F240 recognition of gp41 stumps or misfolded Env variants present on virions rather than its ability to recognize functional gp41 transition structures emerging on trimeric Env post CD4 receptor engagement.

Highlights

Antibody-dependent cell-mediated cytotoxicity (ADCC) by non-neutralizing antibodies specific to the HIV envelope (Env) glycoproteins present at the surface of virus sensitized or infected cells plays a role in the effective adaptive immune response to HIV
The HIV-1 envelope glycoprotein gp[41] traverses at least four sequential conformational states leading to fusion of the viral and target cell membranes
While a number of studies have used synthetic peptides or short recombinant gp[41] proteins to mimic Conformational state 3 (CS3) and CS440,41, including atomic structures, there is no data about the conformation of the disulfide loop region (DLR) in the context of these conformational states

Summary

Introduction

Antibody-dependent cell-mediated cytotoxicity (ADCC) by non-neutralizing antibodies (nnAbs) specific to the HIV envelope (Env) glycoproteins present at the surface of virus sensitized or infected cells plays a role in the effective adaptive immune response to HIV. Our structural studies reveal details of the F240-gp[41] interface and describe a structure of DLR that is distinct from known conformations of this region studied in the context of either CD4-unliganded Env trimer or the gp[41] peptide in the unbound state These data coupled with binding and functional analyses indicate that F240 recognizes non-trimeric Env forms which are significantly overexpressed on intact virions but poorly represented at surfaces of cells infected with infectious molecular clones and endogenously-infected CD4 T cells from HIV-1-infected individuals. Transitional epitopes mapped to the gp[120] subunit within the first and second constant (C1-C2) region (the A32-like epitopes or Cluster A epitopes[3], reviewed in refs 4–6), emerging on virus-sensitized or infected cell surfaces during the conformational rearrangements of Env post CD4 binding, were shown to be targeted by antibodies capable of potent antibody-dependent cell-mediated cytotoxicity (ADCC) without conventional neutralizing activities (refs 3, 7–11, reviewed in refs 4–6). F240 was shown to be broadly cross-reactive and capable of reacting with primary isolates from all clades of HIV-117,20

Methods

Results

Conclusion