Restricted antigenic variability of the epitope recognized by the neutralizing gp41 antibody 2F5

Purtscher, Martin; Trkola, Alexandra; Grassauer, Andreas; Schulz, Petra; Klima, A.; Döpper, Susanne; Grüber, Gerhard; Buchacher, Andrea; Muster, Thomas; Katinger, Hermann

doi:10.1097/00002030-199606000-00003

Cited by 158 publications

(119 citation statements)

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“…1; refs. [12][13][14]. In addition to direct targeting of HIV-1 by neutralizing Abs (15), HIV-1 transcytosis can be blocked by disruption of rafts and by Abs against the ELDKWA epitope (7,8,10,11).…”

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confidence: 99%

A mucosally targeted subunit vaccine candidate eliciting HIV-1 transcytosis-blocking Abs

Matoba

Magérus

Geyer

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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A vaccine that would engage the mucosal immune system against a broad range of HIV-1 subtypes and prevent epithelial transmission is highly desirable. Here we report fusing the mucosal targeting B subunit of cholera toxin to the conserved galactosylceramide-binding domain (including the ELDKWA-neutralizing epitope) of the HIV-1 gp41 envelope protein, which mediates the transcytosis of HIV-1 across the mucosal epithelia. Chimeric protein expressed in bacteria or plants assembled into oligomers that were capable of binding galactosyl-ceramide and G M1 gangliosides. Mucosal (intranasal) administration in mice of the purified chimeric protein followed by an i.p. boost resulted in transcytosis-neutralizing serum IgG and mucosal IgA responses and induced immunological memory. Plant production of mucosally targeted immunogens could be particularly useful for immunization programs in developing countries, where desirable product traits include low cost of manufacture, heat stability, and needle-free delivery.

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confidence: 99%

A mucosally targeted subunit vaccine candidate eliciting HIV-1 transcytosis-blocking Abs

Matoba

Magérus

Geyer

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…Among the most well characterized of these are 1b12 and 2G12, which bind to GP120 (7)(8)(9) and 2F5, which interacts with the COOH-terminal region of GP41 (10). MAb 2F5 has generated much interest because its epitope is well conserved across HIV clades and because of its ability to neutralize both laboratoryadapted and primary viral isolates (11).…”

mentioning

confidence: 99%

Enhancement of α-Helicity in the HIV-1 Inhibitory Peptide DP178 Leads to an Increased Affinity for Human Monoclonal Antibody 2F5 but Does Not Elicit Neutralizing Responses in Vitro

Joyce¹,

Hurni²,

Bogusky

et al. 2002

Journal of Biological Chemistry

113

118

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The synthetic peptide DP178, derived from the carboxyl-terminal heptad repeat region of human immunodeficiency virus type 1 GP41 protein is a potent inhibitor of viral-mediated fusion and contains the sequence ELDKWA, which constitutes the recognition epitope for the broadly neutralizing human monoclonal antibody 2F5. Efforts at eliciting a 2F5-like immune response by immunization with peptides or fusion proteins containing this sequence have not met with success, possibly because of incorrect structural presentation of the epitope. Although the structure of the carboxyl-terminal heptad repeat on the virion is not known, several recent reports have suggested a propensity for ␣-helical conformation. We have examined DP178 in the context of a model for optimized ␣-helices and show that the native sequence conforms poorly to the model. Solution conformation of DP178 was studied by circular dichroism and NMR spectroscopy and found to be predominantly random, consistent with previous reports. NMR mapping was used to show that the low percentage of ␣-helix present was localized to residues Glu 662 through Asn 671 , a region encompassing the 2F5 epitope. Using NH 2 -terminal extensions derived from either GP41 or the yeast GCN4 leucine zipper dimerization domain, we designed peptide analogs in which the average helicity is significantly increased compared with DP178 and show that these peptides exhibit both a modest increase in affinity for 2F5 using a novel competitive solution-based binding assay and an increased ability to inhibit viral entry in a single-cycle infectivity model. Selected peptides were conjugated to carrier protein and used for guinea pig immunizations. High peptide-specific titers were achieved using these immunogens, but the resulting sera were incapable of viral neutralization. We discuss these findings in terms of structural and immunological considerations as to the utility of a 2F5-like response.The HIV-1 1 GP160 envelope glycoprotein is synthesized as a single precursor that is cleaved by a cellular endoprotease to generate two noncovalently associated subunits, GP120 and GP41 (1). GP120 is the receptor-interacting constituent, which mediates sequential binding to the cellular CD4 receptor and CXCR4 or CCR5 chemokine co-receptors. The GP41 transmembrane subunit mediates fusion between viral and cellular membranes (reviewed in Refs. 2 and 3). Both envelope segments are highly immunogenic but antibodies raised by vaccination with full-length or subunit versions of these proteins, while capable of neutralizing homologous virus, are generally not protective against heterologous challenge (4 -6). In contrast, several broadly neutralizing human monoclonal antibodies (mAb) to diverse envelope epitopes have been identified in recent years. Among the most well characterized of these are 1b12 and 2G12, which bind to GP120 (7-9) and 2F5, which interacts with the COOH-terminal region of GP41 (10). MAb 2F5 has generated much interest because its epitope is well conserved across HIV clades and because of it...

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“…447-52D (Gorny et al, 1992) was purchased from Polymun Scientific Immunbiologische Forschung. b12 (Barbas et al, 1992;Burton et al, 1991Burton et al, , 1994Roben et al, 1994), VRC01 (Wu et al, 2010), 17b (Sullivan et al, 1998;Thali et al, 1993;Trkola et al, 1996;Wyatt et al, 1995, 2G12 Crawford et al, 1999;Etemad-Moghadam et al, 1999;Mascola et al, 1999;Trkola et al, 1996), PG16 (Walker et al, 2009) and 2F5 Purtscher et al, 1994Purtscher et al, , 1996 were obtained from the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH.…”

Section: Methodsmentioning

confidence: 99%

Increased HIV-1 sensitivity to neutralizing antibodies by mutations in the Env V3-coding region for resistance to CXCR4 antagonists

Hikichi

Yokoyama

Takemura

et al. 2016

Journal of General Virology

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HIV-1 passage in cell culture in the presence of chemokine receptor antagonists can result in selection of viruses with env mutations that confer resistance to these inhibitors. In the present study, we examined the effect of HIV-1 env mutations that confer resistance to CXCR4 antagonists on envelope (Env) sensitivity to neutralizing antibodies (NAbs). Serial passage of CXCR4-tropic HIV-1 NL4-3 in PM1/CCR5 cells under CXCR4 antagonists KRH-3955, AMD3100 and AMD070 yielded two KRH-3955-resistant, one AMD3100-resistant and one AMD070-resistant viruses. These viruses had multiple env mutations including the Env gp120 V3 region. The majority of viruses having these CXCR4 antagonist-resistant Envs showed higher sensitivity to NAbs 447-52D, b12 and 2F5 targeting the V3 region, the gp120 CD4-binding site and the gp41 membrane proximal region, respectively, compared to NL4-3 WT virus. Recombinant NL4-3 viruses with the V3-coding region replaced with those derived from the CXCR4 antagonist-resistant viruses showed increased sensitivity to NAbs b12, 2F5 and 447-52D. Molecular dynamics simulations of Env gp120 outer domains predicted that the V3 mutations increased levels of fluctuations at the tip and stem of the V3 loop. These results indicate that mutations in the V3-coding region that result in loss of viral sensitivity to CXCR4 antagonists increase viral sensitivity to NAbs, providing insights into our understanding of the interplay of viral Env accessibility to chemokine receptors and sensitivity to NAbs.

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Restricted antigenic variability of the epitope recognized by the neutralizing gp41 antibody 2F5

Cited by 158 publications

References 0 publications

A mucosally targeted subunit vaccine candidate eliciting HIV-1 transcytosis-blocking Abs

A mucosally targeted subunit vaccine candidate eliciting HIV-1 transcytosis-blocking Abs

Enhancement of α-Helicity in the HIV-1 Inhibitory Peptide DP178 Leads to an Increased Affinity for Human Monoclonal Antibody 2F5 but Does Not Elicit Neutralizing Responses in Vitro

Increased HIV-1 sensitivity to neutralizing antibodies by mutations in the Env V3-coding region for resistance to CXCR4 antagonists

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