Paring Down HIV Env: Design and Crystal Structure of a Stabilized Inner Domain of HIV-1 gp120 Displaying a Major ADCC Target of the A32 Region

William D Tolbert,Neelakshi Gohain,Maxime Veillette,Jean-Philippe Chapleau,Chiara Orlandi,Maria L Visciano,Maryam Ebadi,Anthony L Devico,Timothy R Fouts,Andrés Finzi,George K Lewis,Marzena Pazgier

doi:10.1016/j.str.2016.03.005

William D Tolbert, Neelakshi Gohain + Show 10 more

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SummaryEvidence supports a role of antibody-dependent cellular cytotoxicity (ADCC) toward transitional epitopes in the first and second constant (C1-C2) regions of gp120 (A32-like epitopes) in preventing HIV-1 infection and in vaccine-induced protection. Here, we describe the first successful attempt at isolating the inner domain (ID) of gp120 as an independent molecule that encapsulates the A32-like region within a minimal structural unit of the HIV-1 Env. Through structure-based design, we developed ID2, which consists of the ID expressed independently of the outer domain and stabilized in the CD4-bound conformation by an inter-layer disulfide bond. ID2 expresses C1-C2 epitopes in the context of CD4-triggered full-length gp120 but without any known neutralizing epitope present. Thus, ID2 represents a novel probe for the analysis and/or selective induction of antibody responses to the A32 epitope region. We also present the crystal structure of ID2 complexed with mAb A32, which defines its epitope.

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Numerous studies have indicated a relevant role for Fc receptor (FcR)-effector functions including antibody-dependent cellular cytotoxicity (ADCC) in protective immunity, as these responses have been shown to correlate with slower progression of HIV disease (Jia et al, 2013; Wren et al, 2013) or decreased virus replication
Design and Purification of an Independent Inner Domain Molecule, ID1 Our previous structural analysis of complexes formed between A32-like monoclonal Abs (mAbs) and the gp120 antigen indicated that A32-like mAbs invariantly recognize the epitope surface around the b1, b2 strands and the a0 and a1 helices of layers 1 and 2 of the inner domain (ID) of gp120 in its CD4-bound conformation (Acharya et al, 2014; Gohain et al, 2015)
We hypothesized that an independent ID molecule, with the V1V2 loop deleted and preferentially stabilized in the CD4-bound conformation, would be a suitable minimal structure for presenting A32-like epitopes with the same antigenic features as seen in gp120-CD4 complexes

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Numerous studies have indicated a relevant role for Fc receptor (FcR)-effector functions including antibody-dependent cellular cytotoxicity (ADCC) in protective immunity, as these responses have been shown to correlate with slower progression of HIV disease (Jia et al, 2013; Wren et al, 2013) or decreased virus replication. The A32-like entry targets become exposed during the initial steps of viral entry after Env trimers engage the host CD4 receptor and, possibly, the co-receptor They persist on newly infected cell surfaces for extended periods of time (Finnegan et al, 2001, 2002; Mengistu et al, 2015) where they have the capacity to mediate Fc-effector functions in vitro (Guan et al, 2013; reviewed in Lewis et al, 2014; Pollara et al, 2013; Veillette et al, 2016). The picture is even stronger for vaccine-induced immunity in humans, as the A32-like

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