MOLECULAR PROFILE OF AN ANTIBODY-RESPONSE TO HIV-1 AS PROBED BY COMBINATORIAL LIBRARIES

被引:203
作者
BARBAS, CF
COLLET, TA
AMBERG, W
ROBEN, P
BINLEY, JM
HOEKSTRA, D
CABABA, D
JONES, TM
WILLIAMSON, RA
PILKINGTON, GR
HAIGWOOD, NL
CABEZAS, E
SATTERTHWAIT, AC
SANZ, I
BURTON, DR
机构
[1] SCRIPPS RES INST, DEPT IMMUNOL, LA JOLLA, CA 92037 USA
[2] CHIRON CORP, EMERYVILLE, CA 94608 USA
[3] UNIV TEXAS, HLTH SCI CTR, DEPT MED, SAN ANTONIO, TX 78284 USA
[4] UNIV TEXAS, HLTH SCI CTR, DEPT CELLULAR & STRUCT BIOL, SAN ANTONIO, TX 78284 USA
关键词
HUMAN ANTIBODIES; COMBINATORIAL LIBRARIES; ANTIBODY RESPONSE; ANTIBODIES TO HIV;
D O I
10.1006/jmbi.1993.1203
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A large number (33) of human Fab fragments reacting with HIV-1 surface glycoprotein gp120 have been generated by selection from a combinatorial TgG1k library displayed on the surface of phage. The library was prepared from a long term asymptomatic HIV-seropositive donor. Analysis of the sequences from these Fabs shows the heavy chains can be placed in groups, many of which contain intraclonal variants, almost certainly corresponding to chains used in vivo. Further variants can be accessed via chain shuffling experiments in which a given light chain is recombined with a library of heavy chains. Heavy chain promiscuity, i.e. the ability of heavy chains to pair with different light chains with retention of antigen binding, is dependent on the particular heavy chain considered and probably excludes the identification of in vivo light chain partners. The antibodies examined here are primarily to the CD4 binding site on gp120 and broadly reflect the serum profile of the donor. The antibodies show evidence of extensive somatic modification indicative of an antigen-driven response. The heavy chain CDR3 regions of the antibodies show a remarkably conserved extended length. A number also show strong sequence conservation in CDR3 against a background of considerable diversity in the rest of the VH gene supporting a central role for this region in antigen recognition. © 1993 Academic Press, Inc.
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页码:812 / 823
页数:12
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