Scheid JF, Mouquet H, Feldhahn N, Seaman MS, Velinzon K, Pietzsch J et al.Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals. Nature 458:636-640

Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA.
Nature (Impact Factor: 41.46). 05/2009; 458(7238):636-40. DOI: 10.1038/nature07930
Source: PubMed


Antibodies to conserved epitopes on the human immunodeficiency virus (HIV) surface protein gp140 can protect against infection in non-human primates, and some infected individuals show high titres of broadly neutralizing immunoglobulin (Ig)G antibodies in their serum. However, little is known about the specificity and activity of these antibodies. To characterize the memory antibody responses to HIV, we cloned 502 antibodies from HIV envelope-binding memory B cells from six HIV-infected patients with broadly neutralizing antibodies and low to intermediate viral loads. We show that in these patients, the B-cell memory response to gp140 is composed of up to 50 independent clones expressing high affinity neutralizing antibodies to the gp120 variable loops, the CD4-binding site, the co-receptor-binding site, and to a new neutralizing epitope that is in the same region of gp120 as the CD4-binding site. Thus, the IgG memory B-cell compartment in the selected group of patients with broad serum neutralizing activity to HIV is comprised of multiple clonal responses with neutralizing activity directed against several epitopes on gp120.

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Available from: Richard Wyatt, Feb 11, 2014
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    • "). To determine whether these antibodies with limited activity (tier-1 strains only; here termed tier-1 neutralizing antibodies) are active against viruses that carry bNAb escape mutations, we assayed a panel of 34 tier-1 neutralizing mAbs directed against the V2 or the V3 loop, the CD4bs, the CD4-induced site (CD4i), and gp41 (Scheid et al., 2009; Pietzsch et al., 2010; Mouquet et al., 2011). Each of these antibodies was tested against WT HIV-1 YU2 and bNAb-resistant variants of HIV-1 YU2 with mutations that naturally arose in in vivo experiments (single mutations: N160K, N332K, and N280Y; HIV-1 YU2 triple mutations: TM1-3; Fig. 4 B; Klein et al., 2012; Horwitz et al., 2013). "
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    ABSTRACT: Antibody-mediated immunotherapy is effective in humanized mice when combinations of broadly neutralizing antibodies (bNAbs) are used that target nonoverlapping sites on the human immunodeficiency virus type 1 (HIV-1) envelope. In contrast, single bNAbs can control simian-human immunodeficiency virus (SHIV) infection in immune-competent macaques, suggesting that the host immune response might also contribute to the control of viremia. Here, we investigate how the autologous antibody response in intact hosts can contribute to the success of immunotherapy. We find that frequently arising antibodies that normally fail to control HIV-1 infection can synergize with passively administered bNAbs by preventing the emergence of bNAb viral escape variants.
    Full-text · Article · Nov 2014 · Journal of Experimental Medicine
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    • "447-52D [91] was purchased from Polymun Scientific. Expression plasmids for antibody 1.79 [92] were provided by Dr. Michel Nussenzweig, The Rockefeller University, New York, USA. Antibody 1.79 was produced by expression in 293-F cells followed by purification of the antibody by protein G affinity chromatography and size exclusion chromatography as described [13]. "
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    ABSTRACT: Background Variable loops 1 and 2 (V1V2) of the HIV-1 envelope glycoprotein gp120 perform two key functions: ensuring envelope trimer entry competence and shielding against neutralizing antibodies. While preserving entry functionality would suggest a high need for V1V2 sequence optimization and conservation, shielding efficacy is known to depend on a high flexibility of V1V2 giving rise to its substantial sequence variability. How entry competence of the trimer is maintained despite the continuous emergence of antibody escape mutations within V1V2 has not been resolved. Since HIV cell-cell transmission is considered a highly effective means of virus dissemination, we investigated whether cell-cell transmission may serve to enhance infectivity of V1V2 variants with debilitated free virus entry.ResultsIn a detailed comparison of wt and V1V2 mutant envelopes, V1V2 proved to be a key factor in ascertaining free virus infectivity, with V1V2 mutants displaying significantly reduced trimer integrity. Despite these defects, cell-cell transmission was able to partially rescue infectivity of V1V2 mutant viruses. We identified two regions, encompassing amino acids 156 to 160 (targeted by broadly neutralizing antibodies) and 175 to 180 (encompassing the ¿4ß7 binding site) which were particularly prone to free virus infectivity loss upon mutation but maintained infectivity in cell-cell transmission. Of note, V1V2 antibody shielding proved important during both free virus infection and cell-cell transmission.Conclusions Based on our data we propose a model for V1V2 evolution that centers on cell-cell transmission as a salvage pathway for virus replication. Escape from antibody neutralization may frequently result in V1V2 mutations that reduce free virus infectivity. Cell-cell transmission could provide these escape viruses with sufficiently high replication levels that enable selection of compensatory mutations, thereby restoring free virus infectivity while ensuring antibody escape. Thus, our study highlights the need to factor in cell-cell transmission when considering neutralization escape pathways of HIV-1.
    Full-text · Article · Sep 2014 · Retrovirology
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    • "Humoral response against HIV has been well studied and allowed to characterize neutralizing antibodies (NAb) described for their ability to efficiently neutralize a broad range of HIV-1 strains in vitro. Recently, novel broadly NAb (e.g.VRC01, PGT family, 3BNC117, 10-1074, etc) capable of neutralizing a large spectrum of HIV-1 isolates of various clades have been discovered, in addition to the previously well characterized NAb b12, 2G12, 447-52D, 2F5, 4E104567891011. These Ab efficiently inhibit HIV-1 primary isolates or pseudoviruses in vitro in conventional neutralization assay with PBMC or TZM-bl cells. "
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    ABSTRACT: Plasmacytoid dendritic cells (pDC) expressing FcγRIIa are antigen-presenting cells able to link innate and adaptive immunity and producing various cytokines and chemokines. Although highly restricted, they are able to replicate HIV-1. We determined the activity of anti-HIV-1 neutralizing antibodies (NAb) and non-neutralizing inhibitory antibodies (NNIAb) on the infection of primary pDC by HIV-1 primary isolates and analyzed cytokines and chemokines production. Neutralization assay was performed with primary pDC in the presence of serial antibodies (Ab) concentrations. In parallel, we measured the release of cytokines and chemokines by ELISA and CBA Flex assay. We found that NAb, but not NNIAb, inhibit HIV-1 replication in pDC. This inhibitory activity was lower than that detected for myeloid dendritic cells (mDC) infection and independent of FcγRIIa expressed on pDC. Despite the complete protection, IFN-α production was detected in the supernatant of pDC treated with NAb VRC01, 4E10, PGT121, 10-1074, 10E8, or polyclonal IgG44 but not with NAb b12. Production of MIP-1α, MIP-1β, IL-6, and TNF-α by pDC was also maintained in the presence of 4E10, b12 and VRC01. These findings suggest that pDC can be protected from HIV-1 infection by both NAb and IFN-α release triggered by the innate immune response during infection.
    Full-text · Article · Aug 2014 · Scientific Reports
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