       Document 0051
 DOCN  M9640051
 TI    Characterization of the variable regions of a chimpanzee monoclonal
       antibody with potent neutralizing activity against HIV-1.
 DT    9604
 AU    Vijh-Warrier S; Murphy E; Yokoyama I; Tilley SA; Public Health Research
       Institute, New York 10016, USA.
 SO    Mol Immunol. 1995 Oct;32(14-15):1081-92. Unique Identifier : AIDSLINE
       GENBANK/X59315
 AB    The variable (V) regions of C108G, a potent neutralizing chimpanzee mAb
       against a glycan-dependent epitope in the V2 region of HIV-1 gp120, have
       been characterized for reactivity with human VH and VK family-specific
       antisera, and their nucleotide sequences have been determined and
       analysed. To our knowledge, this is the first study characterizing
       expressed chimpanzee VH and VK genes. Results show that C108G expresses
       members of the VH3 and VK1 families, the largest VH and VK families in
       humans, respectively. Nucleotide and amino acid sequence analyses reveal
       that C108G VH is most homologous to the human VH3 germline gene,
       hsigdp33 or V3-43, and the human JH4 minigene. The human germline VK1
       gene that is most homologous to C108G VK, hsigk1012, was previously
       observed in unmutated form in a human autoantibody with anti-i red blood
       cell antigen specificity and in seven human Fabs and a mAb directed
       against epitopes overlapping the CD4-binding site of HIV-1 gp120. This
       germline gene was unmutated in three of the human Fabs and was
       somatically mutated in the other four Fabs and the mAb. In addition, the
       JK minigene was used in C108G VK, JK2, is apparently over-represented in
       anti-HIV-1 mAbs/Fabs; this minigene was used in 61% of the anti-gp120
       human Fabs recently described and in three other anti-CD4-binding site
       human mAbs derived by EBV transformation. While the significance of
       these findings is unclear, they may suggest a bias in VK/JK gene usage
       and/or network regulation involving an hsigk1012/JK2 idiotope(s) in the
       antibody response to HIV-1. Both the C108G VH and VK genes showed
       evidence of somatic mutation and antigen selection that apparently
       occurred in vivo during chronic exposure to HIV-1 and its antigens.
       Surprisingly, this somatic mutation was most profound in the CDR3 region
       of C108G VK; this region shared only 48% nucleotide homology with
       hsigk1012 contrasted with a homology of 94% over the remainder of these
       two V gene sequences. Perhaps the most significant finding of this study
       is that the expressed VH and VK genes of chimpanzee mAb C108G are no
       more divergent from their most homologous human germline genes than are
       the expressed V genes of several recently characterized human anti-HIV-1
       mAbs/Fabs from their apparent human germline genes. This suggests that
       chimpanzee mAbs are no more likely to elicit deleterious
       anti-immunoglobulin responses in humans than are human mAbs and
       emphasizes the potential for development of chimpanzee mAbs as
       immunotherapeutic agents.
 DE    Amino Acid Sequence  Animal  Antibodies, Monoclonal/GENETICS/*ISOLATION
       & PURIF/PHARMACOLOGY  Base Sequence  Chimpansee troglodytes  Cloning,
       Molecular  Human  HIV Antibodies/GENETICS/*ISOLATION &
       PURIF/PHARMACOLOGY  HIV-1/*IMMUNOLOGY  Immunoglobulin Variable
       Region/GENETICS/*ISOLATION & PURIF  Immunoglobulins,
       Heavy-Chain/GENETICS/ISOLATION & PURIF  Immunoglobulins,
       Light-Chain/GENETICS/ISOLATION & PURIF  Molecular Sequence Data
       *Neutralization Tests  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).

