Human antibody responses to HIV type 1 glycoprotein 41 cloned in phage display libraries suggest three major epitopes are recognized and give evidence for conserved antibody motifs in antigen binding

被引:68
作者
Binley, JM
Ditzel, HJ
Barbas, CF
Sullivan, N
Sodroski, J
Parren, PWHI
Burton, DR
机构
[1] Scripps Res Inst, DEPT IMMUNOL IMM2, LA JOLLA, CA 92037 USA
[2] SCRIPPS RES INST, DEPT MOLEC BIOL, LA JOLLA, CA 92037 USA
[3] DANA FARBER CANC INST, DEPT PATHOL, BOSTON, MA 02115 USA
关键词
D O I
10.1089/aid.1996.12.911
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
A large panel of human Fab fragments against the gp41 subunit of the HIV-1 envelope glycoprotein was isolated by panning six phage-displayed antibody libraries against recombinant gp41. The libraries were prepared from HIV-1-seropositive donors, Twenty-three Fabs recognizing conformation-dependent determinants on gp41 were isolated, Further selection of libraries against (1) gp41 ligated with Fabs from the initial selection and against (2) a recombinant gp41-containing gp140 protein yielded five additional Fabs, Competition of members of the Fab panel with one another and with previously described antibodies revealed a series of overlapping specificities that were conveniently grouped into three major epitope clusters. The majority of Fabs recognized epitopes involving residues 649-668 (previously known as the cluster II region), numbered using the Los Alamos LAI sequence, A second set of Fabs reacted with an epitope involving residues 584-609 (known as the cluster I region), Another set of Fabs appeared to recognize a third conformational epitope that has been termed the cluster III region. This third Fab epitope group demonstrated some overlap with both clusters I and II in binding assays, None of the Fabs neutralized HIV-1 laboratory strains at biologically significant concentrations, This tends to support the opinion that a vaccine based on the gp41 molecule has the drawback that neutralizing epitopes of gp41 are rare and/or unfavorably presented to the immune system, Analysis of heavy chain sequences revealed common CDR3 motif sequences in several antibodies, which appears to be an interesting consequence of a persistent immune response to conserved antigen structures.
引用
收藏
页码:911 / 924
页数:14
相关论文
共 62 条
  • [1] ASSEMBLY OF COMBINATORIAL ANTIBODY LIBRARIES ON PHAGE SURFACES - THE GENE-III SITE
    BARBAS, CF
    KANG, AS
    LERNER, RA
    BENKOVIC, SJ
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1991, 88 (18) : 7978 - 7982
  • [2] RECOMBINANT HUMAN FAB FRAGMENTS NEUTRALIZE HUMAN TYPE-1 IMMUNODEFICIENCY VIRUS INVITRO
    BARBAS, CF
    BJORLING, E
    CHIODI, F
    DUNLOP, N
    CABABA, D
    JONES, TM
    ZEBEDEE, SL
    PERSSON, MAA
    NARA, PL
    NORRBY, E
    BURTON, DR
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1992, 89 (19) : 9339 - 9343
  • [3] MOLECULAR PROFILE OF AN ANTIBODY-RESPONSE TO HIV-1 AS PROBED BY COMBINATORIAL LIBRARIES
    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
    [J]. JOURNAL OF MOLECULAR BIOLOGY, 1993, 230 (03) : 812 - 823
  • [4] Barbas CF., 1991, METHODS COMPANION ME, V2, P119
  • [5] VIRUS ENVELOPE PROTEIN OF HTLV-III REPRESENTS MAJOR TARGET ANTIGEN FOR ANTIBODIES IN AIDS PATIENTS
    BARIN, F
    MCLANE, MF
    ALLAN, JS
    LEE, TH
    GROOPMAN, JE
    ESSEX, M
    [J]. SCIENCE, 1985, 228 (4703) : 1094 - 1096
  • [6] IDENTIFICATION OF HUMAN NEUTRALIZATION-INDUCING REGIONS OF THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ENVELOPE GLYCOPROTEINS
    BROLIDEN, PA
    VONGEGERFELT, A
    CLAPHAM, P
    ROSEN, J
    FENYO, EM
    WAHREN, B
    BROLIDEN, K
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1992, 89 (02) : 461 - 465
  • [7] BUCHACHER A, 1992, VACCINES 92 : MODERN APPROACHES TO NEW VACCINES INCLUDING PREVENTION OF AIDS, P191
  • [8] GENERATION OF HUMAN MONOCLONAL-ANTIBODIES AGAINST HIV-1 PROTEINS - ELECTROFUSION AND EPSTEIN-BARR-VIRUS TRANSFORMATION FOR PERIPHERAL-BLOOD LYMPHOCYTE IMMORTALIZATION
    BUCHACHER, A
    PREDL, R
    STRUTZENBERGER, K
    STEINFELLNER, W
    TRKOLA, A
    PURTSCHER, M
    GRUBER, G
    TAUER, C
    STEINDL, F
    JUNGBAUER, A
    KATINGER, H
    [J]. AIDS RESEARCH AND HUMAN RETROVIRUSES, 1994, 10 (04) : 359 - 369
  • [9] HUMAN-ANTIBODIES FROM COMBINATORIAL LIBRARIES
    BURTON, DR
    BARBAS, CF
    [J]. ADVANCES IN IMMUNOLOGY, VOL 57, 1994, 57 : 191 - 280
  • [10] A LARGE ARRAY OF HUMAN MONOCLONAL-ANTIBODIES TO TYPE-1 HUMAN-IMMUNODEFICIENCY-VIRUS FROM COMBINATORIAL LIBRARIES OF ASYMPTOMATIC SEROPOSITIVE INDIVIDUALS
    BURTON, DR
    BARBAS, CF
    PERSSON, MAA
    KOENIG, S
    CHANOCK, RM
    LERNER, RA
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1991, 88 (22) : 10134 - 10137