Human immunodeficiency virus-1 (HIV-1) gp120 superantigen-binding serum antibodies. A host factor in homosexual HIV-1 transmission.

Townsley-Fuchs, Janet; Kam, Lawrence; Fairhurst, Rick M.; Gange, Stephen J.; Goodglick, Lee; Giorgi, Janis V.; Sidell, Neil; Detels, Roger; Braun, Jonathan

doi:10.1172/jci118979

Cited by 28 publications

(24 citation statements)

References 43 publications

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“…Fragments generated by cleavage at the IgMsensitive Lys 432 -Ala 433 bond are reportedly devoid of CD4 binding activity (46). IgG Abs that bind the gp120 superantigenic site noncovalently are described as resistance factors to HIV infection (8). Initial studies conducted as in Ref.…”

Section: Discussionmentioning

confidence: 99%

“…The wells were treated with 5 g/ml IgM samples in 10 mM sodium phosphate, pH 7.4, 137 mM NaCl, 2.7 mM KCl, 0.05% Tween 20 containing 0.1% skim milk. Detection was with peroxidase-conjugated goat anti-human IgM (1:1,000; Sigma) (8).…”

Section: Methodsmentioning

confidence: 99%

“…an antigen recognized by Abs without the requirement for adaptive sequence diversification of the V domains. A weak correlation between IgG Abs that recognize gp120 as a superantigen and resistance to HIV infection has been noted (8). In infected subjects, gp120 induces the synthesis of Abs directed mainly to antigenic epitopes located in the mutable regions of gp120 (9).…”

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confidence: 99%

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Naturally Occurring Proteolytic Antibodies

Paul

Karle

Planque

et al. 2004

Journal of Biological Chemistry

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We report the selective catalytic cleavage of the HIV coat protein gp120, a B cell superantigen, by IgM antibodies (Abs) from uninfected humans and mice that had not been previously exposed to gp120. The rate of IgMcatalyzed gp120 cleavage was greater than of other polypeptide substrates, including the bacterial superantigen protein A. The kinetic parameters of gp120 cleavage varied over a broad range depending on the source of the IgMs, and turnover numbers as great as 2.1/min were observed, suggesting that different Abs possess distinct gp120 recognition properties. IgG Abs failed to cleave gp120 detectably. The Fab fragment of a monoclonal IgM cleaved gp120, suggesting that the catalytic activity belongs to the antibody combining site. The electrophoretic profile of gp120 incubated with a monoclonal human IgM suggested hydrolysis at several sites. One of the cleavage sites was identified as the Lys 432 -Ala 433 peptide bond, located within the region thought to be the Ab-recognizable superantigenic determinant. A covalently reactive peptide analog (CRA) corresponding to gp120 residues 421-431 with a C-terminal amidino phosphonate diester mimetic of the Lys 432 -Ala 433 bond was employed to probe IgM nucleophilic reactivity. The peptidyl CRA inhibited the IgM-catalyzed cleavage of gp120 and formed covalent IgM adducts at levels exceeding a control hapten CRA devoid of the peptide sequence. These observations suggest that IgMs can selectively cleave gp120 by a nucleophilic mechanism and raise the possibility of their role as defense enzymes.As the first class of Abs 1 synthesized in the course of B cell development, IgM Abs often contain V domains that are close in sequence to germ line V genes. IgG Abs produced by differentiated B cells, in comparison, contain V domains that are more diversified by adaptive maturational processes occurring after exposure to the antigen. Recently, we reported that IgM subunits expressed as components of the B cell receptor account for the majority of the nucleophilic reactivity of the B cell surface, detected as the irreversible binding of haptenic covalently reactive antigen analogs (CRAs) containing an electrophilic phosphonate diester group (1). The phosphonate CRAs serve as probes for the activated nucleophiles found in non-Ab proteolytic enzymes (2) and proteolytic Abs (3). Secreted IgM Abs were reported to bind the CRAs irreversibly and catalyze the hydrolysis of model peptide substrates at rates exceeding those of IgG Abs (1). There was no expectation in these studies of selective catalytic cleavage of individual peptide antigens by the IgMs because no attempts were made to induce specific Ab responses by immunization procedures. Indeed, the proteolytic reaction was characterized by its promiscuity, in that tripeptide and tetrapeptide substrates with no apparent sequence similarity were cleaved, limited only by the requirement for a basic residue at the cleavage site (1). In contrast, in the case of specific IgG Abs directed to individual antigens, noncovalent Ab-antigen...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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Naturally Occurring Proteolytic Antibodies

Paul

Karle

Planque

et al. 2004

Journal of Biological Chemistry

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“…This indicates that these IgA NAbs might have potential as a topical microbicide. Despite their lower catalytic activity [56], serum IgM and IgG NAbs to these conserved epitopes in gp120 might also contribute to resistance against HIV infections [57].…”

Section: B and T Cellsmentioning

confidence: 99%

Naturally occurring auto-antibodies in homeostasis and disease

Lutz

Binder

Kaveri

2009

Trends in Immunology

166

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“…IgG Abs that bind the gp120 superantigenic site noncovalently have previously been suggested as resistance factors to the infection [76]. Trimeric gp120 expressed on the HIV surface is responsible for binding to host cell CD4 receptors as the first step in the infection cycle.…”

Section: Homeostatic Functionmentioning

confidence: 99%