       Document 0413
 DOCN  M9490413
 TI    Immunization with a soluble CD4-gp120 complex preferentially induces
       neutralizing anti-human immunodeficiency virus type 1 antibodies
       directed to conformation-dependent epitopes of gp120.
 DT    9411
 AU    Kang CY; Hariharan K; Nara PL; Sodroski J; Moore JP; IDEC
       Pharmaceuticals Corporation, San Diego, California 92121.
 SO    J Virol. 1994 Sep;68(9):5854-62. Unique Identifier : AIDSLINE
       MED/94335102
 AB    Preservation of the conformation of recombinant gp120 in an adjuvant,
       enabling it to elicit conformation-dependent, epitope-specific, broadly
       neutralizing antibodies, may be critical for the development of any
       gp120-based human immunodeficiency virus type 1 (HIV-1) vaccine. It was
       hypothesized that recombinant gp120 complexed with recombinant CD4 could
       stabilize the conformation-dependent neutralizing epitopes and
       effectively deliver them to the immune system. Therefore, a soluble
       CD4-gp120 complex in Syntex adjuvant formulation was tested with mice
       for its ability to induce neutralizing anti-gp120 antibody responses.
       Seventeen monoclonal antibodies (MAbs) were generated and characterized.
       Immunochemical studies, neutralization assays, and mapping studies with
       gp120 mutants indicated that the 17 MAbs fell into three groups. Four of
       them were directed to what is probably a conformational epitope
       involving the C1 domain and did not possess virus-neutralizing
       activities. Another four MAbs bound to V3 peptide 302-321 and exhibited
       cross-reactive gp120 binding and relatively weak virus-neutralizing
       activities. These MAbs were very sensitive to amino acid substitutions,
       not only in the V3 regions but also in the base of the V1/V2 loop,
       implying a conformational constraint on the epitope. The last group of
       nine MAbs recognized conformation-dependent epitopes near the CD4
       binding site of gp120 and inhibited the gp120-soluble CD4 interaction.
       Four of these nine MAbs showed broadly neutralizing activities against
       multiple laboratory-adapted strains of HIV-1, three of them neutralized
       only HIVIIIB, and the two lower-affinity MAbs did not neutralize any
       strain tested. Collectively, the results from this study indicate that
       immunization with the CD4-gp120 complex can elicit antibodies to
       conformationally sensitive gp120 epitopes, with some of the antibodies
       having broadly neutralizing activities. We suggest that immunization
       with CD4-gp120 complexes may be worth evaluating further for the
       development of an AIDS vaccine.
 DE    Animal  Antibodies, Monoclonal/IMMUNOLOGY  Antigenic Determinants
       Antigens, CD4/*IMMUNOLOGY  HIV Antibodies/*IMMUNOLOGY  HIV Envelope
       Protein gp120/*IMMUNOLOGY/ULTRASTRUCTURE  HIV-1/*IMMUNOLOGY
       Macromolecular Systems  Mice  Mice, Inbred BALB C  Neutralization Tests
       Protein Binding  Protein Conformation  Recombinant Proteins  Solubility
       Support, Non-U.S. Gov't  Support, U.S. Gov't, P.H.S.  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

