Document Detail

Immunogenicity of an eight amino acid domain shared by Fas (CD95/Apo-I) and HIV-1 gp120. I. Structural and antigenic analysis.
MedLine Citation:
PMID:  10972086     Owner:  NLM     Status:  MEDLINE    
Previous studies have demonstrated that immunoglobulin G (IgG) antibodies to VEINCTR-N, a domain shared by Fas (CD95/Apo-I) and gp120, contribute to T-cell apoptosis during human immunodeficiency virus-type 1 (HIV-1) infection as a result of the agonist cross-linking of Fas. The present work was designed to determine whether these molecules are elicited primarily to HIV-1 or the cell receptor. MATERIALS AND METHODS: Sera from 439 HIV-1-infected patients were screened by ELISA for their reactivity to VEINCTR-N. Subjects with significant serum elevations of IgG anti-VEINCTR-N were further investigated. Immunologic parameters, including CD4+ and CD8+ lymphocyte count, extent of T-cell apoptosis, occurrence of both anti-Fas antibodies and circulating soluble Fas titers, and reactivity to the 8-mer peptides resembling the flank-regions of VEINCTR-N on both gp120 V3 loop and Fas were examined. In addition, the antigenicity of these domains was assessed by biochemical and computerized analyses. RESULTS: 21 patients with significant levels of IgG to VEINCTR-N showed both an increased extent of peripheral T-cell apoptosis and binding to full-length Fas. A weak, though positive correlation of the anti-VEINCTR-N activity with its antecedent peptide on Fas was also found. Charge and structural analysis revealed that, although the extended 26-amino acid (a.a.) regions on both proteins were hydrophilic, the Fas peptide adjacent to VEINCTR-N expressed a short beta-conformed a.a. sequence in contiguity with a portion of the shared epitope, also in beta-sheet conformation. Patterns of antigenicity confirmed an apparent immunodominance of the full VEINCTR-N, based on its homology with the consensus sequence of other members of the tumor necrosis factor (TNF) receptor family. The hypothesis that the high immunogenicity of this region of Fas, rather than gp120, can drive the production of anti-VEINCTR-N antibodies also was supported by the concurrent significant elevations of soluble Fas in almost all of the sera studied. CONCLUSIONS: Our results indicate that a high release of the soluble form of Fas by T cells during the chronic immune activation of HIV-1 infection primes a humoral response against this epitope of Fas as a result of its high antigenicity. This is similar to the antibodies to tumor necrosis factor alpha (TNFalpha) receptor (R) (TNFalpha-R) that occur in response to increased levels of the soluble receptor for TNF during autoimmunity.
F Silvestris; T Cocco; P Cafforio; N Calvani; F Dammacco
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Molecular medicine (Cambridge, Mass.)     Volume:  6     ISSN:  1076-1551     ISO Abbreviation:  Mol. Med.     Publication Date:  2000 Jun 
Date Detail:
Created Date:  2000-10-06     Completed Date:  2000-10-06     Revised Date:  2008-11-20    
Medline Journal Info:
Nlm Unique ID:  9501023     Medline TA:  Mol Med     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  494-508     Citation Subset:  IM; X    
Department of Biomedical Sciences and Human Oncology, University of Bari, Italy.
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MeSH Terms
Amino Acid Sequence
Antigens, CD95 / chemistry*,  genetics,  immunology*
Apoptosis / immunology
HIV Antibodies / immunology
HIV Envelope Protein gp120 / chemistry*,  genetics,  immunology*
HIV Infections / immunology,  pathology
Immunodominant Epitopes / chemistry,  genetics
Immunoglobulin G / immunology
Models, Molecular
Molecular Sequence Data
Protein Structure, Tertiary / genetics
Sequence Homology, Amino Acid
Reg. No./Substance:
0/Antigens, CD95; 0/HIV Antibodies; 0/HIV Envelope Protein gp120; 0/Immunodominant Epitopes; 0/Immunoglobulin G

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