Catalytic antibodies to HIV: Physiological role and potential clinical utility

Department of Pathology, University of Texas-Houston Medical School, Houston, TX, USA.
Autoimmunity Reviews (Impact Factor: 7.93). 07/2008; 7(6):473-9. DOI: 10.1016/j.autrev.2008.04.002
Source: PubMed


Immunoglobulins (Igs) in uninfected humans recognize residues 421-433 located in the B cell superantigenic site (SAg) of the HIV envelope protein gp120 and catalyze its hydrolysis by a serine protease-like mechanism. The catalytic activity is encoded by germline Ig variable (V) region genes, and is expressed at robust levels by IgMs and IgAs but poorly by IgGs. Mucosal IgAs are highly catalytic and neutralize HIV, suggesting that they constitute a first line of defense against HIV. Lupus patients produce the Igs at enhanced levels. Homology of the 421-433 region with an endogenous retroviral sequence and a bacterial protein may provide clues about the antigen driving anti-SAg synthesis in lupus patients and uninfected subjects. The potency and breadth of HIV neutralization revives hopes of clinical application of catalytic anti-421-433 Igs as immunotherapeutic and topical microbicide reagents. Adaptive improvement of anti-SAg catalytic Igs in HIV infected subjects is not customary. Further study of the properties of the naturally occurring anti-SAg catalytic Igs should provide valuable guidance in designing a prophylactic vaccine that amplifies protective catalytic immunity to HIV.

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    • "Infected humans and animals immunized with gp120 rarely generate class-switched neutralizing antibodies to the CD4BD core by adaptive immune mechanism (Sun et al., 1989; Kelker et al., 2010). It may be hypothesized that vulnerable epitopes essential for microbial survival have evolved superantigenic character as an immune evasion mechanism that precludes an efficient adaptive antibody response (Goodyear and Silverman, 2005; Planque et al., 2008). Rapid induction of B cell adaptive immunity is a stochastic process driven by certain high probability cellular signaling pathways. "
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    ABSTRACT: The immunodominant epitopes expressed by the HIV-1 envelope protein gp120 are hypermutable, defeating attempts to develop an effective HIV vaccine. Targeting the structurally conserved gp120 determinant that binds host CD4 receptors (CD4BD) and initiates infection is a more promising route to vaccination, but this has proved difficult because of the conformational flexibility of gp120 and immune evasion mechanisms used by the virus. Mimicking the outer CD4BD conformational epitopes is difficult because of their discontinuous nature. The CD4BD region composed of residues 421-433 (CD4BD(core)) is a linear epitope, but this region possesses B cell superantigenic character. While superantigen epitopes are vulnerable to a small subset of spontaneously produced neutralizing antibodies present in humans without infection (innate antibodies), their non-covalent binding to B cell receptors (BCRs) does not stimulate an effective adaptive response from B cells. Covalent binding at naturally occurring nucleophilic sites of the BCRs by an electrophilic gp120 (E-gp120) analog is a promising solution. E-gp120 induces the synthesis of neutralizing antibodies the CD4BD(core). The highly energetic covalent reaction is hypothesized to convert the abortive superantigens-BCR interaction into a stimulatory signal, and the binding of a spatially distinct epitope at the traditional combining site of the BCRs may furnish a second stimulatory signal. Flexible synthetic peptides can detect pre-existing CD4BD(core)-specific neutralizing antibodies. However, induced-fit conformational transitions of the peptides dictated by the antibody combining site structure may induce the synthesis of non-neutralizing antibodies. Successful vaccine targeting of the CD4BD will require a sufficiently rigid immunogen that mimics the native epitope conformation and bypasses B cell checkpoints restricting synthesis of the neutralizing antibodies.
    Frontiers in Immunology 12/2012; 3:383. DOI:10.3389/fimmu.2012.00383
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    • "These antibodies, now named as "abzymes", were first obtained in 1986 (Pollack, Jacobs, & Schultz, 1986; Tramontano, Janda, & Lerner, 1986), the first example of natural abzymes was IgG found in bronchial asthma patients, cleaving intestinal vasoactive peptide (Paul et al., 1989). Abzyme's properties were discussed in more detail in recent reviews (Belogurov, Kozyr, Ponomarenko, & Gabibov, 2009; Georgy A. Nevinsky & Buneva, 2005; Planque et al., 2008; Taguchi et al., 2008). Abzymes were detected in human organism at a variety of autoimmune and nonautoimmune pathologies (Gabibov, Ponomarenko, Tretyak, Paltsev, & Suchkov, 2006; G. A. Nevinsky & Buneva, 2003), and various peptides, proteins, nucleic acids and oligosaccharides can serve as substrates for the catalytically active antibodies in human and other mammalians (Hanson, Nishiyama, & Paul, 2005; Lacroix-Desmazes et al., 2006). "

    Autoimmune Disorders - Pathogenetic Aspects, 10/2011; , ISBN: 978-953-307-643-0
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    • "Relevant research suggests that a catalytic antibody-based approach could be a key tool in selective chemotherapeutic strategies against some cancers and HIV-1 (Planque et al., 2008). Naturally-occurring DNA hydrolytic anti-DNA antibodies are apparently linked to various autoimmune and lymphoproliferative disorders, like systemic lupus erythematosus (SLE), multiple sclerosis, Sjogren syndrome, B-chronic lymphocytic leucosis and multiple myeloma. "
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    ABSTRACT: Specific entities of naturally-occurring DNA hydrolytic/cytotoxic antibodies (abzymes) are linked to autoimmune and lymphoproliferative disorders. Suggested sequence of underlying activities conform to such entities penetrating the living cells, trans-locating to nucleus and recognising specific binding sites within single- or double-stranded DNA. Their origin is unknown since corresponding immunogens are unidentified. These anti-DNA antibodies could be the organism's immune response to microbial attack. Their structure, function and pathogenicity were investigated in wet-lab and via bioinformatics in context of Rational Vaccine Designs. This paper offers a comprehensive critical review on the subject in the light of known and newly proposed concepts.
    International Journal of Bioinformatics Research and Applications 08/2011; 7(3):220-38. DOI:10.1504/IJBRA.2011.041735
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