Molecular analysis of HIV-1 gp120 antibody response using isotype IgM and IgG phage display libraries from a long-term non-progressor HIV-1-infected individual.
To characterize the variable heavy chain (VH)3 antibody response to HIV-1 gp120, we analyzed a panel of IgM and IgG1 Fab fragments from phage display isotype libraries from a long-term, non-progressor HIV-1-infected individual. The IgM Fab antibodies isolated had low affinity for gp120, were not restricted to a particular VH3 germ-line gene, and consisted mainly of unmutated VH genes. In contrast, IgG Fab fragments were gp120 specific, with high affinity and extensive somatic mutation; all were clonally related and were derived from a single VH3 germ-line gene (DP50). One IgG Fab (S8) has DP50 VH region nucleotide substitutions identical to those of IgM Fab M025 and uses similar DH and JH segments, suggesting that S8 arose from M025 by isotype switching. In addition, somatic mutation in the IgG heavy chain third complementarity-determining region results in a 100-fold affinity increase for gp120, which correlates with a similar increase in neutralization capacity. These results imply that in vivo IgM to IgG isotype switch and affinity maturation may be important for protection and long-term survival in certain HIV-1-infected individuals.
Torán
J L
JL
Department of Immunology and Oncology, Centro Nacional de Biotecnología, CSIC/UAM, Campus de Cantoblanco, Madrid, Spain.
Kremer
L
L
Sánchez-Pulido
L
L
de Alborán
I M
IM
del Real
G
G
Llorente
M
M
Valencia
A
A
de Mon
M A
MA
Martínez-A
C
C
D000595:Amino Acid Sequence; D000888:Antibodies, Anti-Idiotypic / Q000737:chemistry; D000911:Antibodies, Monoclonal / Q000737:chemistry; D000914:Antibodies, Viral / Q000096:biosynthesis*; D001435:Bacteriophages / Q000235:genetics; D001483:Base Sequence; D022801:Complementarity Determining Regions; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D006679:HIV Seropositivity; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000096:biosynthesis / Q000737:chemistry; D007074:Immunoglobulin G / Q000737:chemistry* / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000737:chemistry* / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000096:biosynthesis; D008969:Molecular Sequence Data; D019151:Peptide Library; D020033:Protein Isoforms / Q000096:biosynthesis / Q000737:chemistry
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D022801:Complementarity Determining Regions; D015699:HIV Envelope Protein gp120; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D019151:Peptide Library; D020033:Protein Isoforms