A potent, neutralizing human monoclonal antibody against a unique epitope overlapping the CD4-binding site of HIV-1 gp120 that is broadly conserved across North American and African virus isolates.
A human monoclonal antibody (HuMAb), 5145A, against HIV-1 gp120 was isolated from an asymptomatic, seropositive hemophiliac. The epitope of this HuMAb was destroyed by reduction of gp120 disulfide bonds, but not by removal of N-linked carbohydrates. This epitope overlaps the CD4-binding site of gp120, because binding of 5145A to gp120 is inhibited by soluble CD4 and by 1125H, a previously described HuMAb directed toward the CD4-binding site. However, the 5145A epitope differs from those of 1125H and other anti-CD4-binding site HuMAbs previously described, as documented by the viral strain specificity of 5145A and its reactivity with a panel of gp120 mutants. Specifically, 5145A reacted with 14 of 15 HIV-1 isolates tested, including 9 isolates from the Central African Republic, 6 of which were not recognized by 1125H. Partial epitope mapping of 5145A, using a series of gp120 mutants, demonstrated its lack of sensitivity to mutations in residues 257 and 427, contrasting with a marked sensitivity to mutations in residues 368 and 370. This pattern of reactivity distinguishes its epitope from that of any HuMAb against the CD4-binding site region described to date. In addition, 5145A exhibited potent and essentially equivalent neutralization of the MN, SF-2, IIIB, and RF strains and possessed significant neutralizing activity against three of three African strains tested. Finally, 5145A synergistically neutralized the MN and SF-2 strains of HIV-1 when combined with 4117C, a HuMAb against the V3 loop. The broad strain specificity and potent neutralizing activity of 5145A, together with its ability to synergize with an anti-V3 loop HuMAb in neutralizing HIV-1, indicate that 5145A has excellent potential as a passive immunotherapeutic agent against HIV-1.
Pinter
A
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Public Health Research Institute, New York, New York 10016.
Honnen
W J
WJ
Racho
M E
ME
Tilley
S A
SA
D000163:Acquired Immunodeficiency Syndrome / Q000453:epidemiology; D000911:Antibodies, Monoclonal / Q000276:immunology*; D001666:Binding Sites, Antibody; D001667:Binding, Competitive; D015153:Blotting, Western; D015704:CD4 Antigens / Q000276:immunology*; D002488:Central African Republic / Q000453:epidemiology; D003429:Cross Reactions; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000276:immunology*; D015686:Gene Products, env / Q000276:immunology; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology* / Q000302:isolation & purification; D006801:Humans; D009500:Neutralization Tests; D009656:North America / Q000453:epidemiology
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D000939:Epitopes; D015686:Gene Products, env; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120