Broadly neutralizing antibodies targeted to the membrane-proximal external region of human immunodeficiency virus type 1 glycoprotein gp41

被引:683
作者
Zwick, MB
Labrijn, AF
Wang, M
Spenlehauer, C
Saphire, EO
Binley, JM
Moore, JP
Stiegler, G
Katinger, H
Burton, DR
Parren, PWHI
机构
[1] Scripps Res Inst, Dept Immunol IMM 2, La Jolla, CA 92037 USA
[2] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA
[3] Cornell Univ, Weill Med Coll, Dept Microbiol & Immunol, New York, NY USA
[4] Agr Univ Vienna, Inst Appl Microbiol, A-1180 Vienna, Austria
关键词
D O I
10.1128/JVI.75.22.10892-10905.2001
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
The identification and epitope mapping of broadly neutralizing anti-human immunodeficiency virus type 1 (HIV-1) antibodies (Abs) is important for vaccine design, but, despite much effort, very few such Abs have been forthcoming. Only one broadly neutralizing anti-gp41 monoclonal Ab (MAb), 2F5, has been described. Here we report on two MAbs that recognize a region immediately C-terminal of the 2F5 epitope. Both MAbs were generated from HIV-1-seropositive donors, one (Z13) from an antibody phage display library, and one (4E10) as a hybridoma. Both MAbs recognize a predominantly linear and relatively conserved epitope, compete with each other for binding to synthetic peptide derived from gp41, and bind to HIV-1(MN) virions. By flow cytometry, these MAbs appear to bind relatively weakly to infected cells and this binding is not perturbed by pretreatment of the infected cells with soluble CD4. Despite the apparent linear nature of the epitopes of Z13 and 4E10, denaturation of recombinant envelope protein reduces the binding of these MAbs, suggesting some conformational requirements for full epitope expression. Most significantly, Z13 and 4E10 are able to neutralize selected primary isolates from diverse subtypes of HIV-1 (e.g., subtypes B, C, and E). The results suggest that a rather extensive region of gp41 close to the transmembrane domain is accessible to neutralizing Abs and could form a useful target for vaccine design.
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页码:10892 / 10905
页数:14
相关论文
共 81 条
[1]   Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian-human immunodeficiency virus infection [J].
Baba, TW ;
Liska, V ;
Hofmann-Lehmann, R ;
Vlasak, J ;
Xu, WD ;
Ayehunie, S ;
Cavacini, LA ;
Posner, MR ;
Katinger, H ;
Stiegler, G ;
Bernacky, BJ ;
Rizvi, TA ;
Schmidt, R ;
Hill, LR ;
Keeling, ME ;
Lu, YC ;
Wright, JE ;
Chou, TC ;
Ruprecht, RM .
NATURE MEDICINE, 2000, 6 (02) :200-206
[2]  
Barbas 3rd C. F., 2001, PHAGE DISPLAY LAB MA
[3]   RECOMBINANT HUMAN FAB FRAGMENTS NEUTRALIZE HUMAN TYPE-1 IMMUNODEFICIENCY VIRUS INVITRO [J].
BARBAS, CF ;
BJORLING, E ;
CHIODI, F ;
DUNLOP, N ;
CABABA, D ;
JONES, TM ;
ZEBEDEE, SL ;
PERSSON, MAA ;
NARA, PL ;
NORRBY, E ;
BURTON, DR .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1992, 89 (19) :9339-9343
[4]   MOLECULAR PROFILE OF AN ANTIBODY-RESPONSE TO HIV-1 AS PROBED BY COMBINATORIAL LIBRARIES [J].
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 .
JOURNAL OF MOLECULAR BIOLOGY, 1993, 230 (03) :812-823
[5]   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 [J].
Binley, JM ;
Ditzel, HJ ;
Barbas, CF ;
Sullivan, N ;
Sodroski, J ;
Parren, PWHI ;
Burton, DR .
AIDS RESEARCH AND HUMAN RETROVIRUSES, 1996, 12 (10) :911-924
[6]   A recombinant human immunodeficiency virus type 1 envelope glycoprotein complex stabilized by an intermolecular disulfide bond between the gp120 and gp41 subunits is an antigenic mimic of the trimeric virion-associated structure [J].
Binley, JM ;
Sanders, RW ;
Clas, B ;
Schuelke, N ;
Master, A ;
Guo, Y ;
Kajumo, F ;
Anselma, DJ ;
Maddon, PJ ;
Olson, WC ;
Moore, JP .
JOURNAL OF VIROLOGY, 2000, 74 (02) :627-643
[7]   GENERATION OF HUMAN MONOCLONAL-ANTIBODIES AGAINST HIV-1 PROTEINS - ELECTROFUSION AND EPSTEIN-BARR-VIRUS TRANSFORMATION FOR PERIPHERAL-BLOOD LYMPHOCYTE IMMORTALIZATION [J].
BUCHACHER, A ;
PREDL, R ;
STRUTZENBERGER, K ;
STEINFELLNER, W ;
TRKOLA, A ;
PURTSCHER, M ;
GRUBER, G ;
TAUER, C ;
STEINDL, F ;
JUNGBAUER, A ;
KATINGER, H .
AIDS RESEARCH AND HUMAN RETROVIRUSES, 1994, 10 (04) :359-369
[8]   A LARGE ARRAY OF HUMAN MONOCLONAL-ANTIBODIES TO TYPE-1 HUMAN-IMMUNODEFICIENCY-VIRUS FROM COMBINATORIAL LIBRARIES OF ASYMPTOMATIC SEROPOSITIVE INDIVIDUALS [J].
BURTON, DR ;
BARBAS, CF ;
PERSSON, MAA ;
KOENIG, S ;
CHANOCK, RM ;
LERNER, RA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1991, 88 (22) :10134-10137
[9]   Why do we not have an HIV vaccine and how can we make one? [J].
Burton, DR ;
Moore, JP .
NATURE MEDICINE, 1998, 4 (05) :495-498
[10]   A vaccine for HIV type 1: The antibody perspective [J].
Burton, DR .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (19) :10018-10023