A blueprint for HIV vaccine discovery. Cell Host Microbe

Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA
Cell host & microbe (Impact Factor: 12.19). 10/2012; 12(4):396-407. DOI: 10.1016/j.chom.2012.09.008
Source: PubMed

ABSTRACT Despite numerous attempts over many years to develop an HIV vaccine based on classical strategies, none has convincingly succeeded to date. A number of approaches are being pursued in the field, including building upon possible efficacy indicated by the recent RV144 clinical trial, which combined two HIV vaccines. Here, we argue for an approach based, in part, on understanding the HIV envelope spike and its interaction with broadly neutralizing antibodies (bnAbs) at the molecular level and using this understanding to design immunogens as possible vaccines. BnAbs can protect against virus challenge in animal models, and many such antibodies have been isolated recently. We further propose that studies focused on how best to provide T cell help to B cells that produce bnAbs are crucial for optimal immunization strategies. The synthesis of rational immunogen design and immunization strategies, together with iterative improvements, offers great promise for advancing toward an HIV vaccine.

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Available from: Dennis R Burton, Aug 26, 2015
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    • "To unambiguously define affinity to different Ag variants and to consider complex immunogens that reflect features on viral spikes, we developed a coarse-grained model with ''residuelevel'' resolution for key BCR-Ag interactions (Figure 1C). Our model was inspired by the CD4bs on the trimeric HIV-1 viral spike, which is targeted by many monoclonal bnAbs for HIV-1 (Burton et al., 2012). But, it applies to other epitopes that contain highly conserved residues and can easily be modified to consider other pathogens. "
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    ABSTRACT: Generation of potent antibodies by a mutation-selection process called affinity maturation is a key component of effective immune responses. Antibodies that protect against highly mutable pathogens must neutralize diverse strains. Developing effective immunization strategies to drive their evolution requires understanding how affinity maturation happens in an environment where variants of the same antigen are present. We present an in silico model of affinity maturation driven by antigen variants which reveals that induction of cross-reactive antibodies often occurs with low probability because conflicting selection forces, imposed by different antigen variants, can frustrate affinity maturation. We describe how variables such as temporal pattern of antigen administration influence the outcome of this frustrated evolutionary process. Our calculations predict, and experiments in mice with variant gp120 constructs of the HIV envelope protein confirm, that sequential immunization with antigen variants is preferred over a cocktail for induction of cross-reactive antibodies focused on the shared CD4 binding site epitope. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 02/2015; 160(4). DOI:10.1016/j.cell.2015.01.027 · 33.12 Impact Factor
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    • "Over the past five years, many new broadly neutralizing antibodies (bnAbs) that are able to neutralize diverse panels of HIV-1 in vitro have been isolated from HIV-1-infected humans (Burton et al., 2012b; Huang et al., 2012; Klein et al., 2013; Kwong and Mascola, 2012; Scheid et al., 2011; Walker et al., 2009, 2011; Zhou et al., 2010). These advances have reinvigorated the pursuit of both active and passive HIV-1 vaccine strategies (Barouch et al., 2013; Burton et al., 2012a; Horwitz et al., 2013; Klein et al., 2012b; Shingai et al., 2013). The sole targets for bnAbs are native, functional envelope glycoprotein (Env) trimers on the virus surface. "
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    ABSTRACT: All previously characterized broadly neutralizing antibodies to the HIV-1 envelope glycoprotein (Env) target one of four major sites of vulnerability. Here, we define and structurally characterize a unique epitope on Env that is recognized by a recently discovered family of human monoclonal antibodies (PGT151-PGT158). The PGT151 epitope is comprised of residues and glycans at the interface of gp41 and gp120 within a single protomer and glycans from both subunits of a second protomer and represents a neutralizing epitope that is dependent on both gp120 and gp41. Because PGT151 binds only to properly formed, cleaved trimers, this distinctive property, and its ability to stabilize Env trimers, has enabled the successful purification of mature, cleaved Env trimers from the cell surface as a complex with PGT151. Here we compare the structural and functional properties of membrane-extracted Env trimers from several clades with those of the soluble, cleaved SOSIP gp140 trimer.
    Immunity 04/2014; 40(5). DOI:10.1016/j.immuni.2014.04.008 · 19.75 Impact Factor
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    • "PGT128, and the 10-1074 family), a conformational epitope on gp120 (3BC176), a domain in the vicinity of the CD4bs (8ANC195), and the gp41 membrane-proximal external region (MPER; 2F5, 4E10, and 10E8; Scheid et al., 2009, 2011; Walker et al., 2011; Wu et al., 2011; Kwong and Mascola, 2012; Mouquet et al., 2012; West et al., 2012; Liao et al., 2013). Some of these antibodies display remarkable antiviral activity with median 50% inhibitory concentrations (IC50s) < 0.2 µg/ml for up to 95% of isolates tested (Diskin et al., 2011; Scheid et al., 2011; Walker et al., 2011; Wu et al., 2011; Burton et al., 2012; Liao et al., 2013). The antiviral activity of bNAbs is typically measured in vitro using cell-free pseudovirus particles and reporter cell lines, such as the HeLa-derived TzMbl cell (Heyndrickx et al., 2012). "
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    ABSTRACT: The neutralizing activity of anti-HIV-1 antibodies is typically measured in assays where cell-free virions enter reporter cell lines. However, HIV-1 cell to cell transmission is a major mechanism of viral spread, and the effect of the recently described broadly neutralizing antibodies (bNAbs) on this mode of transmission remains unknown. Here we identify a subset of bNAbs that inhibit both cell-free and cell-mediated infection in primary CD4(+) lymphocytes. These antibodies target either the CD4-binding site (NIH45-46 and 3BNC60) or the glycan/V3 loop (10-1074 and PGT121) on HIV-1 gp120 and act at low concentrations by inhibiting multiple steps of viral cell to cell transmission. These antibodies accumulate at virological synapses and impair the clustering and fusion of infected and target cells and the transfer of viral material to uninfected T cells. In addition, they block viral cell to cell transmission to plasmacytoid DCs and thereby interfere with type-I IFN production. Thus, only a subset of bNAbs can efficiently prevent HIV-1 cell to cell transmission, and this property should be considered an important characteristic defining antibody potency for therapeutic or prophylactic antiviral strategies.
    Journal of Experimental Medicine 11/2013; 210(13). DOI:10.1084/jem.20131244 · 13.91 Impact Factor
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