Enhanced HIV-1 neutralization by a CD4-VH3-IgG1 fusion protein.
HIV-1 gp120 is an alleged B cell superantigen, binding certain VH3+ human antibodies. We reasoned that a CD4-VH3 fusion protein could possess higher affinity for gp120 and improved HIV-1 inhibitory capacity. To test this we produced several human IgG1 immunoligands harboring VH3. Unlike VH3-IgG1 or VH3-CD4-IgG1, CD4-VH3-IgG1 bound gp120 considerably stronger than CD4-IgG1. CD4-VH3-IgG1 exhibited approximately 1.5-2.5-fold increase in neutralization of two T-cell laboratory-adapted strains when compared to CD4-IgG1. CD4-VH3-IgG1 improved neutralization of 7/10 clade B primary isolates or pseudoviruses, exceeding 20-fold for JR-FL and 13-fold for Ba-L. It enhanced neutralization of 4/8 clade C viruses, and had negligible effect on 1/4 clade A pseudoviruses. We attribute this improvement to possible pairing of VH3 with CD4 D1 and stabilization of an Ig Fv-like structure, rather than to superantigen interactions. These novel findings support the current notion that CD4 fusion proteins can act as better HIV-1 entry inhibitors with potential clinical implications.
Meyuhas
Ronit
R
Laboratory of Immunology, MIGAL, Kiryat Shmona 11016, Israel.
Noy
Hava
H
Fishman
Sigal
S
Margalit
Alon
A
Montefiori
David C
DC
Gross
Gideon
G
D000595:Amino Acid Sequence; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology*; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology*; D008024:Ligands; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology*; D018089:Superantigens / Q000276:immunology*
D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D007074:Immunoglobulin G; D007135:Immunoglobulin Variable Region; D008024:Ligands; D011993:Recombinant Fusion Proteins; D018089:Superantigens