HIV therapy by a combination of broadly neutralizing antibodies in humanized mice

Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA.
Nature (Impact Factor: 42.35). 10/2012; 492(7427). DOI: 10.1038/nature11604

ABSTRACT Human antibodies to human immunodeficiency virus-1 (HIV-1) can neutralize a broad range of viral isolates in vitro and protect non-human primates against infection1, 2. Previous work showed that antibodies exert selective pressure on the virus but escape variants emerge within a short period of time3, 4. However, these experiments were performed before the recent discovery of more potent anti-HIV-1 antibodies and their improvement by structure-based design5, 6, 7, 8, 9. Here we re-examine passive antibody transfer as a therapeutic modality in HIV-1-infected humanized mice. Although HIV-1 can escape from antibody monotherapy, combinations of broadly neutralizing antibodies can effectively control HIV-1 infection and suppress viral load to levels below detection. Moreover, in contrast to antiretroviral therapy10, 11, 12, the longer half-life of antibodies led to control of viraemia for an average of 60 days after cessation of therapy. Thus, combinations of potent monoclonal antibodies can effectively control HIV-1 replication in humanized mice, and should be re-examined as a therapeutic modality in HIV-1-infected individuals.

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    • "Moreover, in this study three different bioanalytical approaches for glycoprofiling of human sera are described, including traditional ELISA-like method enzyme-linked lectin assay (ELLA), novel multiplexed lectin microarray format of analysis and ultrasensitive EISbased biosensing with immobilized lectins. Since glycosylation is the most common posttranslational modification of proteins (!50% of all eukaryotic proteins and !70% of all therapeutic proteins) [19] [32] a huge scientific effort is devoted to better understanding of their role in cell processes or to apply such knowledge to design better therapeutics or diagnostic tools [33] [34] [35] [36] [37] [38] [39] [40]. Thus, glycoprofiling of samples from SSc patients can be an alternative way for future early stage diagnostics of the SSc disease and other diseases including various types of cancer associated with aberrant glycosylation. "
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    ABSTRACT: Systemic sclerosis (SSc) is an autoimmune disease seriously affecting patient́s quality of life. The heterogeneity of the disease also means that identification and subsequent validation of biomarkers of the disease is quite challenging. A fully validated single biomarker for diagnosis, prognosis, disease activity and assessment of response to therapy is not yet available. The main aim of this study was to apply an alternative assay protocol to the immunoassay-based analysis of this disease by employment of sialic acid recognizing lectin Sambucus nigra agglutinin (SNA) to glycoprofile serum samples. To our best knowledge this is the first study describing direct lectin-based glycoprofiling of serum SSc samples. Three different analytical methods for glycoprofiling of serum samples relying on application of lectins are compared here from a bioanalytical point of view including traditional ELISA-like lectin-based method (ELLA), novel fluorescent lectin microarrays and ultrasensitive impedimetric lectin biosensors. Results obtained by all three bioanalytical methods consistently showed differences in the level of sialic acid present on glycoproteins, when serum from healthy people was compared to the one from patients having SSc. Thus, analysis of sialic acid content in human serum could be of a diagnostic value for future detection of SSc, but further work is needed to enhance selectivity of assays for example by glycoprofiling of a fraction of human serum enriched in antibodies for individual diagnostics.
    Analytica Chimica Acta 01/2015; 853:555-562. DOI:10.1016/j.aca.2014.10.029 · 4.52 Impact Factor
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    • "In addition to identifying vaccine targets, bNAbs could potentially be used therapeutically in established HIV-1 infections, especially bNAb combinations that limit escape by recognizing nonoverlapping epitopes (Barouch et al., 2013; Klein et al., 2012; Shingai et al., 2013). Potent variants of 8ANC195 may be particularly valuable in this respect because the epitope does not overlap with the targets of CD4-binding site, V1/V2 loop, V3 loop, or MPER antibodies. "
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    ABSTRACT: Broadly neutralizing antibodies (bNAbs) to HIV-1 envelope glycoprotein (Env) can prevent infection in animal models. Characterized bNAb targets, although key to vaccine and therapeutic strategies, are currently limited. We defined a new site of vulnerability by solving structures of bNAb 8ANC195 complexed with monomeric gp120 by X-ray crystallography and trimeric Env by electron microscopy. The site includes portions of gp41 and N-linked glycans adjacent to the CD4-binding site on gp120, making 8ANC195 the first donor-derived anti-HIV-1 bNAb with an epitope spanning both Env subunits. Rather than penetrating the glycan shield by using a single variable-region CDR loop, 8ANC195 inserted its entire heavy-chain variable domain into a gap to form a large interface with gp120 glycans and regions of the gp120 inner domain not contacted by other bNAbs. By isolating additional 8ANC195 clonal variants, we identified a more potent variant, which may be valuable for therapeutic approaches using bNAb combinations with nonoverlapping epitopes.
    Cell Reports 04/2014; 7(3). DOI:10.1016/j.celrep.2014.04.001 · 8.36 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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