A Fusion Intermediate gp41 Immunogen Elicits Neutralizing Antibodies to HIV-1

Lai, Rachel; Hock, M. Benjamin; Radzimanowski, Jens; Tonks, Paul; Hulsik, D. Lutje; Effantin, Grégory; Seilly, David J.; Dreja, Hanna; Kliche, Alexander; Wagner, Ralf; Barnett, Susan W.; Tumba, Nancy; Morris, Lynn; LaBranche, Celia C.; Montefiori, David C.; Seaman, Michael S.; Heeney, Jonathan L.; Weissenhorn, Winfríed

doi:10.1074/jbc.m114.569566

Cited by 36 publications

(36 citation statements)

References 119 publications

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“…Additionally, MPER structure is influenced by membrane lipid composition2930. Therefore, it is widely assumed that the generation of a robust anti-MPER response should require its presentation within a membrane environment to properly present neutralizing determinants and to implement lipid cross-reactivity5559606162.…”

Section: Discussionmentioning

confidence: 99%

Proteoliposomal formulations of an HIV-1 gp41-based miniprotein elicit a lipid-dependent immunodominant response overlapping the 2F5 binding motif

Molinos-Albert

Bilbao

Agulló

et al. 2017

Sci Rep

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The HIV-1 gp41 Membrane Proximal External Region (MPER) is recognized by broadly neutralizing antibodies and represents a promising vaccine target. However, MPER immunogenicity and antibody activity are influenced by membrane lipids. To evaluate lipid modulation of MPER immunogenicity, we generated a 1-Palmitoyl-2-oleoylphosphatidylcholine (POPC)-based proteoliposome collection containing combinations of phosphatidylserine (PS), GM3 ganglioside, cholesterol (CHOL), sphingomyelin (SM) and the TLR4 agonist monophosphoryl lipid A (MPLA). A recombinant gp41-derived miniprotein (gp41-MinTT) exposing the MPER and a tetanus toxoid (TT) peptide that favors MHC-II presentation, was successfully incorporated into lipid mixtures (>85%). Immunization of mice with soluble gp41-MinTT exclusively induced responses against the TT peptide, while POPC proteoliposomes generated potent anti-gp41 IgG responses using lower protein doses. The combined addition of PS and GM3 or CHOL/SM to POPC liposomes greatly increased gp41 immunogenicity, which was further enhanced by the addition of MPLA. Responses generated by all proteoliposomes targeted the N-terminal moiety of MPER overlapping the 2F5 neutralizing epitope. Our data show that lipids impact both, the epitope targeted and the magnitude of the response to membrane-dependent antigens, helping to improve MPER-based lipid carriers. Moreover, the identification of immunodominant epitopes allows for the redesign of immunogens targeting MPER neutralizing determinants.

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Section: Discussionmentioning

confidence: 99%

Proteoliposomal formulations of an HIV-1 gp41-based miniprotein elicit a lipid-dependent immunodominant response overlapping the 2F5 binding motif

Molinos-Albert

Bilbao

Agulló

et al. 2017

Sci Rep

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“…Some of the vaccine candidates evaluated so far include immunogens based on short MPER peptides, either alone or coupled to carrier proteins (Decroix et al, 2001; Joyce, 2002; Liao et al, 2000; Matoba et al, 2006; McGaughey et al, 2003; Ni et al, 2004); the use of artificial scaffolds containing stabilized MPER epitopes (Correia et al, 2010; Guenaga et al, 2011; Ofek et al, 2010); hybrid/fusion proteins (Coëffier et al, 2000; Hinz et al, 2009; Krebs et al, 2014; Law et al, 2007; Liang et al, 1999; Mantis et al, 2001; Strasz et al, 2014); chimeric viruses or virus-like particles displaying MPER epitopes (Arnold et al, 2009; Benen et al, 2014; Bomsel et al, 2011; Eckhart et al, 1996; Jain et al, 2010; Kamdem Toukam et al, 2012; Kim et al, 2007; Luo et al, 2006; Marusic et al, 2001; Muster et al, 1995; Ye et al, 2011; Yi et al, 2013; Zhang et al, 2004); and presentation of MPER peptides on liposomes (Dennison et al, 2011; Hanson et al, 2015; Hulsik et al, 2013; Lai et al, 2014; Matyas et al, 2009; Mohan et al, 2014; Serrano et al, 2014; Venditto et al, 2013; 2014). Despite these efforts, none of them succeeded in inducing bnAbs against the MPER, albeit a few recent studies reported induction of modest levels of cross-clade neutralizing activity (Hulsik et al, 2013; Krebs et al, 2014; Lai et al, 2014; Ye et al, 2011; Yi et al, 2013). These results highlight the difficulty in eliciting anti-MPER bnAbs through vaccination.…”

Section: Introductionmentioning

confidence: 99%

Immunogenic properties of a trimeric gp41-based immunogen containing an exposed membrane-proximal external region

et al. 2015

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The membrane-proximal external region (MPER) of HIV-1 gp41 is an attractive target for vaccine development. Thus, better understanding of its immunogenic properties in various structural contexts is important. We previously described the crystal structure of a trimeric protein complex named gp41-HR1-54Q, which consists of the heptad repeat regions 1 and 2 and the MPER. The protein was efficiently recognized by broadly neutralizing antibodies. Here, we describe its immunogenic properties in rabbits. The protein was highly immunogenic, especially the C-terminal end of the MPER containing 4E10 and 10E8 epitopes (671NWFDITNWLWYIK683). Although antibodies exhibited strong competition activity against 4E10 and 10E8, neutralizing activity was not detected. Detailed mapping analyses indicated that amino acid residues critical for recognition resided on faces of the alpha helix that are either opposite of or perpendicular to the epitopes recognized by 4E10 and 10E8. These results provide critical information for designing the next generation of MPER-based immunogens.

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“…Motifs associated with cellular trafficking (localization, transport, secretion, and sequestration) are readily edited to modify where expression products go, and change interaction profiles with other proteins [14]. In addition to motifs that stabilize the structure of immunogens, such as trimerization ('foldon') [15][16][17][18] and dimerization [19,20] domains, motifs that interact with cellular processes for innate antiviral pathways could be used to enhance immunogenicity. While SLiMs in eukaryotic proteins have been discussed extensively, SLiM involvement in viral immunomodulation remains less thoroughly explored, and suggests new opportunities for use in engineered biotechnology applications.…”

Section: How Viruses Do More With Lessmentioning

confidence: 99%

Resources to Discover and Use Short Linear Motifs in Viral Proteins

Hraber

O’Maille

Silberfarb

et al. 2020

Trends in Biotechnology

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Viral proteins evade host immune function by molecular mimicry, often achieved by short linear motifs (SLiMs) of three to ten consecutive amino acids (AAs). Motif mimicry tolerates mutations, evolves quickly to modify interactions with the host, and enables modular interactions with protein complexes. Host cells cannot easily coordinate changes to conserved motif recognition and binding interfaces under selective pressure to maintain critical signaling pathways. SLiMs offer potential for use in synthetic biology, such as better immunogens and therapies, but may also present biosecurity challenges. We survey viral uses of SLiMs to mimic host proteins, and information resources available for motif discovery. As the number of examples continues to grow, knowledge management tools are essential to help organize and compare new findings.

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A Fusion Intermediate gp41 Immunogen Elicits Neutralizing Antibodies to HIV-1

Cited by 36 publications

References 119 publications

Proteoliposomal formulations of an HIV-1 gp41-based miniprotein elicit a lipid-dependent immunodominant response overlapping the 2F5 binding motif

Proteoliposomal formulations of an HIV-1 gp41-based miniprotein elicit a lipid-dependent immunodominant response overlapping the 2F5 binding motif

Immunogenic properties of a trimeric gp41-based immunogen containing an exposed membrane-proximal external region

Resources to Discover and Use Short Linear Motifs in Viral Proteins

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