IMMUNIZATION WITH A SOLUBLE CD4-GP120 COMPLEX PREFERENTIALLY INDUCES NEUTRALIZING ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ANTIBODIES DIRECTED TO CONFORMATION-DEPENDENT EPITOPES OF GP120
Cy. Kang et al., IMMUNIZATION WITH A SOLUBLE CD4-GP120 COMPLEX PREFERENTIALLY INDUCES NEUTRALIZING ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ANTIBODIES DIRECTED TO CONFORMATION-DEPENDENT EPITOPES OF GP120, Journal of virology, 68(9), 1994, pp. 5854-5862
Preservation of the conformation of recombinant gp120 in an adjuvant,
enabling it to elicit conformation-dependent, epitope-specific, broadl
y neutralizing antibodies, may be critical for the development of any
gpl20-based human immunodeficiency virus type 1 (HIV-1) vaccine. It wa
s hypothesized that recombinant gp120 complexed with recombinant CD3 c
ould stabilize the conformation-dependent neutralizing epitopes and ef
fectively 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-gpl20 antibody responses. Seve
nteen monoclonal antibodies (MAbs) were generated and characterized. I
mmunochemical 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 in
volving the C1 domain and did not possess virus-neutralizing activitie
s. Another four MAbs bound to V3 peptide 302-321 and exhibited cross-r
eactive gp120 binding and relatively weak virus-neutralizing activitie
s. These MAbs were very sensitive to amino acid substitutions, not onl
y 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 CD3 binding site
of gp120 and inhibited the gp120-soluble CD4 interaction. Pour of thes
e nine MAbs showed broadly neutralizing activities against multiple la
boratory-adapted strains of HIV-1, three of them neutralized only HIVI
IIB, and the two lower-affinity MAbs did not neutralize any strain tes
ted. Collectively, the results from this study indicate that immunizat
ion with the CD4-gp120 complex can elicit antibodies to conformational
ly sensitive gp120 epitopes, with some of the antibodies having broadl
y neutralizing activities. We suggest that immunization with CD4-gp120
complexes may be worth evaluating further for the development of an A
IDS vaccine.