The neutralizing antibody response against a conserved region of human immunodeficiency virus type 1 gp41 (amino acid residues 731-752) is uniquely directed against a conformational epitope.

Buratti, Emanuele; McLain, Lesley; Tisminetzky, Sergio; Cleveland, Susan M.; Dimmock, Nigel J.; Baralle, Francisco E.

doi:10.1099/0022-1317-79-11-2709

Cited by 33 publications

(31 citation statements)

References 29 publications

(31 reference statements)

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“…CT reactivity. Although it is thought that the CT of gp41 is contained by the viral membrane, there are several MAbs that recognize a hydrophilic region in the so-called "Kennedy epitope" (PRGPDRPEGIEEEGGERDRDRS) at the N terminus of the CT (aa 724 to 745) (29,44). Two possible structures have been proposed for the CT, with each being adopted as part of drastic conformational changes produced by gp41 during viral infection (41,61).…”

Section: Ab Response Against Gp41mentioning

confidence: 99%

The Membrane-Proximal External Region of the Human Immunodeficiency Virus Type 1 Envelope: Dominant Site of Antibody Neutralization and Target for Vaccine Design

Montero¹,

Houten

Wang³

et al. 2008

Microbiol Mol Biol Rev

233

194

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SUMMARY Enormous efforts have been made to produce a protective vaccine against human immunodeficiency virus type 1; there has been little success. However, the identification of broadly neutralizing antibodies against epitopes on the highly conserved membrane-proximal external region (MPER) of the gp41 envelope protein has delineated this region as an attractive vaccine target. Furthermore, emerging structural information on the MPER has provided vaccine designers with new insights for building relevant immunogens. This review describes the current state of the field regarding (i) the structure and function of the gp41 MPER; (ii) the structure and binding mechanisms of the broadly neutralizing antibodies 2F5, 4E10, and Z13; and (iii) the development of an MPER-targeting vaccine. In addition, emerging approaches to vaccine design are presented.

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Section: Ab Response Against Gp41mentioning

confidence: 99%

The Membrane-Proximal External Region of the Human Immunodeficiency Virus Type 1 Envelope: Dominant Site of Antibody Neutralization and Target for Vaccine Design

Montero¹,

Houten

Wang³

et al. 2008

Microbiol Mol Biol Rev

233

194

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“…1), the foreign epitope would be presented as an immunogen able to elicit antibodies reactive to the native epitope. This system, when used with the V3 loop epitope (35) and the ERDRD conformational epitope of gp41 (6), has yielded results that indicate the important role of the backbone structure of the virus both in fixing a conformation similar to the natural one and in promoting a vigorous antibody response through the heterologous context. Hence, we constructed four recombinant FHV capsid proteins expressing the CCR5 89-102 epitope.…”

Section: Discussionmentioning

confidence: 99%

“…The FHV Epitope Presenting System (6,7,32,35), based on a modified capsid precursor protein of the Flock House virus (FHV), was obtained through the courtesy of F. Baralle (ICGEB, Trieste, Italy). The system is composed of a set of five modified capsid gene sequences (cloned in the expression vector pET-3 [Novagen, Madison, WI]), in each of which the nucleotide sequence corresponding to a peptide loop was replaced by a single Bsu36I restriction site to allow the oriented insertion of a synthetic polynucleotide coding for a foreign epitope in five distinct sites (L1, L2, L3, I2, and I3) ( Fig.…”

Section: Methodsmentioning

confidence: 99%

Induction of Murine Mucosal CCR5-Reactive Antibodies as an Anti-Human Immunodeficiency Virus Strategy

Barassi¹,

Soprana²,

Pastori³

et al. 2005

J Virol

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The genital mucosa is the main site of initial human immunodeficiency virus type 1 (HIV-1) contact with its host. In spite of repeated sexual exposure, some individuals remain seronegative, and a small fraction of them produce immunoglobulin G (IgG) and IgA autoantibodies directed against CCR5, which is probably the cause of the CCR5-minus phenotype observed in the peripheral blood mononuclear cells of these subjects. These antibodies recognize the 89-to-102 extracellular loop of CCR5 in its native conformation. The aim of this study was to induce infection-preventing mucosal anti-CCR5 autoantibodies in individuals at high risk of HIV infection. Thus, we generated chimeric immunogens containing the relevant CCR5 peptide in the context of the capsid protein of Flock House virus, a presentation system in which it is possible to engineer conformationally constrained peptide in a highly immunogenic form. Administered in mice via the systemic or mucosal route, the immunogens elicited anti-CCR5 IgG and IgA (in sera and vaginal fluids). Analogous to exposed seronegative individuals, mice producing anti-CCR5 autoantibodies express significantly reduced levels of CCR5 on the surfaces of CD4 ؉ cells from peripheral blood and vaginal washes. In vitro studies have shown that murine IgG and IgA (i) specifically bind human and mouse CD4؉ lymphocytes and the CCR5-transfected U87 cell line, (ii) down-regulate CCR5 expression of CD4 ؉ cells from both humans and untreated mice, (iii) inhibit Mip-1␤ chemotaxis of CD4 ؉ CCR5 ؉ lymphocytes, and (iv) neutralize HIV R5 strains. These data suggest that immune strategies aimed at generating anti-CCR5 antibodies at the level of the genital mucosa might be feasible and represent a strategy to induce mucosal HIV-protective immunity.

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“…This evidence centres on the use of neutralizing antibody specific for a highly conformational epitope with the sequence (%'ERDRD(&! (Buratti et al, 1998 ;McLain et al, 1996 a, b) (according to the numbering system of Ratner et al, 1985). We showed that (i) ERDRD-specific IgG binds free HIV-1 particles in solution and that this virus remains neutralized after unbound antibody is separated from putative virus-antibody complexes by centrifugation (by using infectivity as the readout, the problem of broken virus particles in which the epitope might be artefactually exposed was avoided) ; (ii) ERDRDspecific IgG failed to bind to protease-treated wt HIV-1 virions ; (iii) a deletion mutant lacking most of the C-terminal gp41 tail was not neutralized, implying that the epitope was present in that location ; and finally, (iv) neutralizing antibody escape mutants selected by growth of virus in the presence of ERDRD-specific antibody carried a single amino acid substitution adjacent to the epitope that eliminated the binding of the selecting antibody (S. M. Cleveland, L. McLain, T. D. Jones, C. Parry and N. J. Dimmock, unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Properties of a neutralizing antibody that recognizes a conformational form of epitope ERDRD in the gp41 C-terminal tail of human immunodeficiency virus type 1

Cleveland

Jones²,

Dimmock

2000

Microbiology

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The possibility that epitopes from the C-terminal tail of the gp41 transmembrane protein of human immunodeficiency virus type 1 (HIV-1) are exposed the surface of the virion has long been contentious. Resolution of this has been hampered by the absence of any neutralizing monoclonal antibodies, but we have recently epitope-purified a neutralizing polyclonal IgG specific for one of the putative gp41 tail epitopes, 746 ERDRD 750 . This was obtained from mice immunized parenterally with a plant virus chimera expressing residues 731-752 from the gp41 tail. The ERDRD epitope is highly conformational and is conserved in 81 % of B clade viruses. Here, it is shown that this polyclonal ERDRD-specific IgG is highly potent, with an affinity of 2n2i10 8 M N1 , and a neutralization rate constant (NK neut ) of 7n8i10 4 M N1 s N1 that exceeds that of nearly all other known HIV-1-neutralizing antibodies. ERDRD-specific IgG gave 50 % neutralization at 0n1-0n2 µg/ml and 90 % neutralization at approximately 3 µg/ml. It also neutralized virus that was already attached to target cells, and this and other data suggest that it neutralized by inhibiting a virion event that precedes the fusion-entry process. Consistent with this conclusion was the finding that neutralizing amounts of ERDRD-specific IgG did not inhibit the attachment of free virus to target cells. ERDRDspecific IgG was also cross-reactive and neutralized all but one of six B clade T cell line-adapted strains tested.

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The neutralizing antibody response against a conserved region of human immunodeficiency virus type 1 gp41 (amino acid residues 731-752) is uniquely directed against a conformational epitope.

Cited by 33 publications

References 29 publications

The Membrane-Proximal External Region of the Human Immunodeficiency Virus Type 1 Envelope: Dominant Site of Antibody Neutralization and Target for Vaccine Design

The Membrane-Proximal External Region of the Human Immunodeficiency Virus Type 1 Envelope: Dominant Site of Antibody Neutralization and Target for Vaccine Design

Induction of Murine Mucosal CCR5-Reactive Antibodies as an Anti-Human Immunodeficiency Virus Strategy

Properties of a neutralizing antibody that recognizes a conformational form of epitope ERDRD in the gp41 C-terminal tail of human immunodeficiency virus type 1

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