Abstract
SummaryEliciting HIV-1-specific broadly neutralizing antibodies (bNAbs) remains a challenge for vaccine development, and the potential of passively delivered bNAbs for prophylaxis and therapeutics is being explored. We used neutralization data from four large virus panels to comprehensively map viral signatures associated with bNAb sensitivity, including amino acids, hypervariable region characteristics, and clade effects across four different classes of bNAbs. The bNAb signatures defined for the variable loop 2 (V2) epitope region of HIV-1 Env were then employed to inform immunogen design in a proof-of-concept exploration of signature-based epitope targeted (SET) vaccines. V2 bNAb signature-guided mutations were introduced into Env 459C to create a trivalent vaccine, and immunization of guinea pigs with V2-SET vaccines resulted in increased breadth of NAb responses compared with Env 459C alone. These data demonstrate that bNAb signatures can be utilized to engineer HIV-1 Env vaccine immunogens capable of eliciting antibody responses with greater neutralization breadth.
Highlights
MethodsMETHOD DETAILSExperimental Methods for Vaccine Evaluation Plasmids, Cell Lines, Protein Production, and Antibodies Our baseline immunogen was the C clade Env 459C, initially selected because it elicited tier 1B NAb responses (Bricault et al, 2015), and subsequently found to induce low levels of select tier 2 NAbs upon evaluation of larger tier 2 pseudovirus panels
There has been some progress in animal models (Escolano et al, 2016; Saunders et al, 2017), but human trials have yet to elicit bNAbs, NAbs with varying levels of breadth arise during natural infection (Hraber et al, 2014b). bNAbs typically develop slowly during chronic infection as the virus diversifies under immune pressure and B cell lineages adapt to the evolving virus (Bonsignori et al, 2017b; Doria-Rose et al, 2014; Liao et al, 2013; Wu et al, 2015). bNAb breadth and potency are evaluated using large panels of HIV-1 Envelope (Env) pseudoviruses that sample global HIV-1 diversity (Hraber et al, 2014a) or the C clade diversity of Southern Africa (Rademeyer et al, 2016)
Signature sites were identified using a strategy that incorporates a phylogenetic correction (Gnanakaran et al, 2010) for amino acids (AAs) and potential N-linked glycosylation sites (PNGSs) (Crispin and Doores, 2015), and we explored the impacts of hypervariable region characteristics
Summary
METHOD DETAILSExperimental Methods for Vaccine Evaluation Plasmids, Cell Lines, Protein Production, and Antibodies Our baseline immunogen was the C clade Env 459C, initially selected because it elicited tier 1B NAb responses (Bricault et al, 2015), and subsequently found to induce low levels of select tier 2 NAbs upon evaluation of larger tier 2 pseudovirus panels. Large scale production of HIV-1 Env gp140 foldon and SOSIPs were produced as described previously (Nkolola et al, 2010, 2014a; Steichen et al, 2016). Peptide Microarrays RepliTope Antigen Collection HIV Ultra slides (JPT Peptide Technologies GmbH) arrays were generated, conducted, and analyzed using methods as described previously (Stephenson et al, 2015). These slides contain linear 15-mer peptides designed utilizing the HIV-1 global sequence database to provide coverage of HIV-1 global sequences (Stephenson et al, 2015). Slides were scanned with a GenePix 4300A scanner (Molecular Devices) and analyzed with GenePix Pro 7 software and
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
