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Antibodies to a superantigenic glycoprotein 120 epitope as the basis for developing an HIV vaccine. | LitMetric

AI Article Synopsis

  • The study investigates the challenges in generating neutralizing antibodies (Abs) targeting the CD4 binding determinant (CD4BD) of HIV's gp120 and suggests these challenges may stem from issues with immunogen binding and antibody mutations.
  • Researchers used peptide analogs of a specific region of gp120 (CD4BD(core)) to isolate antibodies from noninfected humans with lupus, which were able to neutralize various HIV strains, indicating a potential pathway for antibody recognition.
  • The findings suggest that germline-encoded antibodies (constitutive Abs) can effectively target the CD4BD(core) epitope, revealing opportunities for developing more effective HIV vaccines by amplifying this response.

Article Abstract

Failure to induce synthesis of neutralizing Abs to the CD4 binding determinant (CD4BD) of gp120, a central objective in HIV vaccine research, has been alternately ascribed to insufficient immunogen binding to Abs in their germline V region configuration expressed as BCRs, insufficient adaptive mutations in Ab V regions, and conformational instability of gp120. We employed peptide analogs of gp120 residues 421-433 within the CD4BD (CD4BD(core)) to identify Abs produced without prior exposure to HIV (constitutive Abs). The CD4BD(core) peptide was recognized by single-chain Fv fragments from noninfected humans with lupus that neutralized genetically diverse strains belonging to various HIV subtypes. Replacing the framework region (FR) of a V(H)4-family single-chain Fv with the corresponding V(H)3-family FRs from single-chain Fv JL427 improved the CD4BD(core) peptide-binding activity, suggesting a CD4BD(core) binding site outside the pocket formed by the CDRs. Replacement mutations in the FR site vicinity suggested the potential for adaptive improvement. A very small subset of serum CD4BD(core)-specific serum IgAs from noninfected humans without autoimmune disease isolated by epitope-specific chromatography neutralized the virus potently. A CD4BD(core)-specific, HIV neutralizing murine IgM with H and L chain V regions (V(H) and V(L) regions) free of immunogen-driven somatic mutations was induced by immunization with a CD4BD(core) peptide analog containing an electrophilic group that binds B cells covalently. The studies indicate broad and potent HIV neutralization by constitutive Abs as an innate, germline-encoded activity directed to the superantigenic CD4BD(core) epitope that is available for amplification for vaccination against HIV.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3755593PMC
http://dx.doi.org/10.4049/jimmunol.1200981DOI Listing

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