V3-specific neutralizing antibodies in sera from HIV-1 gp160-immunized volunteers block virus fusion and act synergistically with human monoclonal antibody to the conformation-dependent CD4 binding site of gp120. NIH-NIAID AIDS Vaccine Clinical Trials Network.
Sera from 11 volunteers immunized with a recombinant HIV-1 gp160-expressing vaccinia virus (HIVAC-1e; Oncogen/Bristol-Myers Squibb, Seattle, WA) and boosted with baculovirus-derived rgp160 (VaxSyn; MicroGeneSys, Inc., Meriden, CT) were evaluated for functional serum antibodies and their epitopes. Sera obtained prior to boosting had undetectable HIV-1-specific IgG and neutralizing activity, and did not block HIV-1 from binding or fusing to CD4+ MT-2 cells. 14 d after boosting, sera from each volunteer contained HIV-1-specific IgG titers of 1:40 to 1:1,280. Five of these sera also contained neutralizing antibodies, where most or all neutralizing activity was blocked by a synthetic peptide corresponding to amino acids 307-330 of the V3 loop of gp120, indicating that neutralizing antibodies were mostly V3 loop-specific. All sera obtained after boosting contained HIV-1 binding/fusion-inhibition antibodies, and a significant portion of their activity was blocked by the V3 loop peptide, a result consistent with the presence of antibodies against the region of the V3 loop that participates in fusion. Three sera with V3 loop-specific neutralizing and fusion-inhibition antibodies were studied further. In competitive antibody binding experiments, antibodies reactive with the conformation-dependent, CD4 binding site of gp120 were undetectable in each serum. When evaluated in combination with a monoclonal antibody to the CD4 binding site of gp120, two sera demonstrated synergism in neutralizing assays, and all three sera demonstrated synergism in binding/fusion-inhibition assays, further indicating that the functional antibodies were primarily V3 loop-specific. The synergism also suggests that a vaccine that elicits strong serum antibody responses to both regions of gp120 may improve the potential for inducing protective immunity.
Montefiori
D C
DC
Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
Graham
B S
BS
Zhou
J
J
Zhou
J
J
Bucco
R A
RA
Schwartz
D H
DH
Cavacini
L A
LA
Posner
M R
MR
D016915:AIDS Vaccines / Q000276:immunology / Q000494:pharmacology*; D000328:Adult; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D015703:Antigens, CD / Q000378:metabolism*; D001665:Binding Sites; D001667:Binding, Competitive; D015704:CD4 Antigens / Q000378:metabolism*; D002460:Cell Line; D015686:Gene Products, env / Q000276:immunology / Q000494:pharmacology*; D015483:HIV Antibodies / Q000097:blood* / Q000494:pharmacology; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D019302:HIV Envelope Protein gp160; D015497:HIV-1 / Q000276:immunology / Q000502:physiology*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood* / Q000494:pharmacology; D008561:Membrane Fusion / Q000187:drug effects / Q000276:immunology; D009500:Neutralization Tests; D011498:Protein Precursors / Q000276:immunology / Q000494:pharmacology*; D014614:Vaccines, Synthetic / Q000276:immunology / Q000494:pharmacology*; D014616:Vaccinia virus / Q000276:immunology
D016915:AIDS Vaccines; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015704:CD4 Antigens; D015686:Gene Products, env; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D019302:HIV Envelope Protein gp160; D007074:Immunoglobulin G; D011498:Protein Precursors; D014614:Vaccines, Synthetic