Antigenicity and immunogenicity of the HIV-1 gp41 epitope ELDKWA inserted into permissive sites of the MalE protein

Coëffier, Eliane; Clément, Jean-Marie; Cussac, V.; Khodaei-Boorane, Nasser; Jéhanno, Muguette; Rojas, Marie; Dridi, Abel; Latour, Mireille; Habib, Raphaëlle El; Barré‐Sinoussi, Françoise; Hofnung, Maurice; Leclerc, Claude

doi:10.1016/s0264-410x(00)00267-x

Cited by 119 publications

(91 citation statements)

References 23 publications

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“…On the other hand, NAbs that target the MPER of gp41 are rare in infected individuals, suggesting that such epitopes are weakly immunogenic [28,[63][64][65][66]. Many gp41 antibodies are raised against the membrane-distal immunodominant epitope I (residue 597-613) and immunodominant epitope II (residue 644-663) regions and are incapable of mediating viral neutralization [67][68][69].…”

Section: Discussionmentioning

confidence: 99%

“…In addition to simple linear or structurally constrained peptide immunogens, recombinant protein immunogens including displays of constrained 2F5 epitope in the contexts of various protein scaffolds have been also pursued [28][29][30][31][32][33][34][35][36][37]. While inducing high antibody titers against the primary amino acid sequence of the epitope, these immunogens have failed to elicit NAbs against primary HIV-1.…”

Section: Introductionmentioning

confidence: 99%

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Immunogenicity of recombinant human immunodeficiency virus type 1-like particles expressing gp41 derivatives in a pre-fusion state

Kim

Qiao

et al. 2007

Vaccine

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The conserved membrane proximal external region (MPER) of the ectodomain of human immunodeficiency virus type 1 (HIV-1) gp41 is the target of two broadly neutralizing antibodies, 2F5 and 4E10. However, no neutralizing antibodies have been elicited against immunogens bearing these epitopes. Given that structural and biochemical studies suggest that the lipid membrane of the virion is involved in their proper configuration, HIV-1 gp41 derivatives in a pre-fusion state were expressed on the surface of immature virus like particles (VLP) derived from Sf9 cells. Guinea pigs were immunized with three doses of VLPs or Sf9 cells presenting gp41 derivatives with or without E. coli heat-labile enterotoxin (LT) as an adjuvant. While immune sera contained high titer anti-VLP antibodies, the specific anti-gp41 antibody responses were low with no neutralizing antibodies detected. An explanation for this absence may be the low level of gp41 expression relative to the many other proteins derived from host cells which are incorporated onto the VLP surface. In addition, the anti-gp41 immune response was preferentially directed to the C-helical domain, away from the MPER. Future vaccine design needs to contend with the complexity of epitope display as well as immunodominance.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Immunogenicity of recombinant human immunodeficiency virus type 1-like particles expressing gp41 derivatives in a pre-fusion state

Kim

Qiao

et al. 2007

Vaccine

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“…The ability of anti-ELDKWA Abs to block viral transmission in vivo by passive immunization in the macaque model (17,18) further illuminates the importance of inducing Abs against this region as part of a prophylactic HIV-1 vaccine. However, elicitation of an Ab response against the linear ELDKWA epitope has proved difficult (28,40).…”

Section: Discussionmentioning

confidence: 99%

“…2 and 3), we assume that self-association of the P1 domain and consequent reconstitution of the lectin-binding site are also possible in the context of the fusion protein, similar to the case of the free peptide (and presumably the corresponding region of gp41). Thus, the CTB-P1 immunogen presented here contains a modality, which simple ELDKWA epitope fusions lack (40).…”

Section: Discussionmentioning

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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“…MPER-specific broadly neutralizing antibodies are rarely made in HIV-1 infection (2-4), but recent studies from our group and others have shown that 2F5-like antibodies responsible for neutralization breadth can be found in ≈0.3% of HIV-1 infected subjects (5), whereas 4E10-like antibodies can be found in ∼3% of HIV-1 positive subjects (6). Vaccination with antigenic envelope constructs expressing 2F5 and 4E10 epitopes has not induced high-titered neutralizing antibodies (7)(8)(9)(10). One hypothesis for the failure of such vaccines to elicit broadly neutralizing antibodies is that the Env epitopes presented to host B cells are not in the correct envelope conformation; for the MPER, this conformation may be the transient, prehairpin gp41 intermediate (11,12).…”

Section: Immunogen | Broadly Neutralizing Antibodiesmentioning

confidence: 95%

Prolonged exposure of the HIV-1 gp41 membrane proximal region with L669S substitution

Shen

Dennison

Liu

et al. 2010

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

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The conserved membrane-proximal external region (MPER) of HIV-1 envelope is a target for the rare broadly neutralizing 2F5, Z13, and 4E10 monoclonal antibodies (mAbs). One strategy to elicit such antibodies is to design an immunogen with increased exposure of the 2F5 and 4E10 mAb epitopes. In this study we characterize a single leucine to serine substitution at position 669 (L669S) in the gp41 Env MPER that confers >250-fold more neutralization sensitivity to 2F5 and 4E10 mAbs than does the wild-type gp41 sequence. On synthetic liposomes, increased solvent exposure of MPER tryptophan residues and stable docking of 2F5 and 4E10 mAbs to mutant MPER peptide liposomes indicate more favorable membrane orientation of MPER neutralizing epitopes with L669S substitution. The time during which virus is sensitive to 2F5 mAb-mediated neutralization is approximately 3-fold longer when the mutation is present. These data suggest that a major contribution to the L669S mutant virus phenotype of enhanced susceptibility to MPER mAbs is prolonged exposure of the MPER neutralizing epitope during viral entry. immunogen | broadly neutralizing antibodiesA major challenge for an effective HIV-1 vaccine is the inability of immunogens to induce broadly neutralizing antibodies (nAbs). One goal for antibody-based HIV-1 vaccine strategies is to elicit broadly neutralizing antibodies similar in breadth to the membrane-proximal external region (MPER) 2F5 and 4E10 monoclonal antibodies (mAbs) that neutralize a majority of transmitted viruses (1). MPER-specific broadly neutralizing antibodies are rarely made in HIV-1 infection (2-4), but recent studies from our group and others have shown that 2F5-like antibodies responsible for neutralization breadth can be found in ≈0.3% of HIV-1 infected subjects (5), whereas 4E10-like antibodies can be found in ∼3% of HIV-1 positive subjects (6). Vaccination with antigenic envelope constructs expressing 2F5 and 4E10 epitopes has not induced high-titered neutralizing antibodies (7-10). One hypothesis for the failure of such vaccines to elicit broadly neutralizing antibodies is that the Env epitopes presented to host B cells are not in the correct envelope conformation; for the MPER, this conformation may be the transient, prehairpin gp41 intermediate (11,12). Another hypothesis is that 2F5 and 4E10 mAbs, which are unusual in having long hydrophobic CDR3 loops, may be particularly effective in reaching epitopes near the virion lipid bilayer, but may be difficult to induce because of down-regulation of polyreactive B cell clones through B cell tolerance mechanisms (13-18).Previous work has identified two amino acid substitutions (T569A, I675V) (19) and L669S (5) in the MPER that increased neutralization sensitivity by MPER antibodies; however, the mechanism by which neutralization sensitivity was increased was not determined (5,19). We now report that the mechanism of enhanced neutralization sensitivity of a single amino acid substitution (leucine to serine substitution at position 669, L669S) in the heptad re...

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Antigenicity and immunogenicity of the HIV-1 gp41 epitope ELDKWA inserted into permissive sites of the MalE protein

Cited by 119 publications

References 23 publications

Immunogenicity of recombinant human immunodeficiency virus type 1-like particles expressing gp41 derivatives in a pre-fusion state

Immunogenicity of recombinant human immunodeficiency virus type 1-like particles expressing gp41 derivatives in a pre-fusion state

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

Prolonged exposure of the HIV-1 gp41 membrane proximal region with L669S substitution

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