Potent neutralization of primary HIV-1 isolates by antibodies directed against epitopes present in the V1/V2 domain of HIV-1 gp120.

Although it is known that some human immune sera possess potent neutralizing activities for primary viruses, the identity of the target epitopes mediating this neutralization is unknown, and currently available immunogens have not been able to induce such activities. Using recombinant fusion glycoproteins expressing native V1/V2 domains of gp120 we have found that sera from a subset of HIV-1-infected humans contain antibodies that recognize broadly conserved V1/V2 epitopes. Such antibodies were isolated from one human serum by affinity chromatography on a column containing a V1/V2 fusion protein, and shown to efficiently neutralize several macrophage-tropic HIV-1 isolates. Rodents immunized with the purified V1/V2 fusion protein produced antibodies reactive with unrelated V1/V2 fusion proteins and with heterologous gp120s. V1/V2-specific immunoglobulins isolated from sera of these animals by affinity chromatography also possessed potent neutralization activity for several primary HIV-1 isolates. These results indicate that the V1/V2 domain of HIV-1 gp120 contains conserved epitopes that mediate potent neutralization of primary viruses, and suggest that subunit vaccines that efficiently induce such antibodies may provide protective humoral immunity against clinically relevant HIV-1 isolates.

[1]  Anthony S. Fauci,et al.  Toward an Understanding of the Correlates of Protective Immunity to HIV Infection , 1996, Science.

[2]  A. Trkola,et al.  Human monoclonal antibody 2G12 defines a distinctive neutralization epitope on the gp120 glycoprotein of human immunodeficiency virus type 1 , 1996, Journal of virology.

[3]  P. Berman,et al.  Cryptic nature of envelope V3 region epitopes protects primary monocytotropic human immunodeficiency virus type 1 from antibody neutralization , 1994, Journal of virology.

[4]  C. Barbas,et al.  Primary isolates of human immunodeficiency virus type 1 are relatively resistant to neutralization by monoclonal antibodies to gp120, and their neutralization is not predicted by studies with monomeric gp120 , 1995, Journal of virology.

[5]  D. Birx,et al.  Differential role of V3-specific antibodies in neutralization assays involving primary and laboratory-adapted isolates of HIV type 1. , 1995, AIDS research and human retroviruses.

[6]  D. Ho,et al.  Sequence diversity of V1 and V2 domains of gp120 from human immunodeficiency virus type 1: lack of correlation with viral phenotype , 1995, Journal of virology.

[7]  E. Emini,et al.  Neutralization of divergent human immunodeficiency virus type 1 variants and primary isolates by IAM-41-2F5, an anti-gp41 human monoclonal antibody. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[8]  J. Mascola,et al.  Potent and synergistic neutralization of human immunodeficiency virus (HIV) type 1 primary isolates by hyperimmune anti-HIV immunoglobulin combined with monoclonal antibodies 2F5 and 2G12 , 1997, Journal of virology.

[9]  G. Shaw,et al.  Macrophage tropism determinants of human immunodeficiency virus type 1 in vivo , 1992, Journal of virology.

[10]  W. Blattner,et al.  Temporal analysis of the antibody response to HIV envelope protein in HIV-infected laboratory workers. , 1994, The Journal of clinical investigation.

[11]  J. Moore,et al.  Rat monoclonal antibodies to nonoverlapping epitopes of human immunodeficiency virus type 1 gp120 block CD4 binding in vitro. , 1991, Virology.

[12]  F. Graham,et al.  Characteristics of a human cell line transformed by DNA from human adenovirus type 5. , 1977, The Journal of general virology.

[13]  Ying Sun,et al.  Replicative function and neutralization sensitivity of envelope glycoproteins from primary and T-cell line-passaged human immunodeficiency virus type 1 isolates , 1995, Journal of virology.

[14]  T. Hideshima,et al.  An IgG human monoclonal antibody that reacts with HIV-1/GP120, inhibits virus binding to cells, and neutralizes infection. , 1991, Journal of immunology.

[15]  Q. Sattentau,et al.  Identification of the residues in human CD4 critical for the binding of HIV , 1989, Cell.

[16]  J. McKeating,et al.  Characterization of neutralization epitopes in the V2 region of human immunodeficiency virus type 1 gp120: role of glycosylation in the correct folding of the V1/V2 domain , 1995, Journal of virology.

[17]  Q. Sattentau,et al.  Probing the structure of the V2 domain of human immunodeficiency virus type 1 surface glycoprotein gp120 with a panel of eight monoclonal antibodies: human immune response to the V1 and V2 domains , 1993, Journal of virology.

[18]  S. Zolla-Pazner,et al.  Neutralization of primary human immunodeficiency virus type 1 isolates by the broadly reactive anti-V3 monoclonal antibody, 447-52D , 1994, Journal of virology.

[19]  D. King,et al.  High-Level Expression of a Recombinant Antibody from Myeloma Cells Using a Glutamine Synthetase Gene as an Amplifiable Selectable Marker , 1992, Bio/Technology.

[20]  A. Pinter,et al.  Synergistic neutralization of human immunodeficiency virus type 1 by a chimpanzee monoclonal antibody against the V2 domain of gp120 in combination with monoclonal antibodies against the V3 loop and the CD4-binding site , 1996, Journal of virology.

[21]  R. M. Hendry,et al.  Neutralization of primary HIV‐1 isolates by anti‐envelope monoclonal antibodies , 1995, AIDS.

[22]  D. Ho,et al.  High concentrations of recombinant soluble CD4 are required to neutralize primary human immunodeficiency virus type 1 isolates. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[23]  D. Burke,et al.  Relative inefficiency of soluble recombinant CD4 for inhibition of infection by monocyte-tropic HIV in monocytes and T cells. , 1990, Journal of immunology.

[24]  R. Orentas,et al.  Involvement of a leukocyte adhesion receptor (LFA-1) in HIV-induced syncytium formation. , 1989, Science.

[25]  G Himmler,et al.  A conserved neutralizing epitope on gp41 of human immunodeficiency virus type 1 , 1993, Journal of virology.

[26]  B. Korber,et al.  Inter- and intraclade neutralization of human immunodeficiency virus type 1: genetic clades do not correspond to neutralization serotypes but partially correspond to gp120 antigenic serotypes , 1996, Journal of virology.

[27]  D. Volsky,et al.  Redefinition of tropism of common macrophage-tropic human immunodeficiency virus type 1. , 1995, AIDS research and human retroviruses.

[28]  D. Ho,et al.  Conformational epitope on gp120 important in CD4 binding and human immunodeficiency virus type 1 neutralization identified by a human monoclonal antibody , 1991, Journal of virology.

[29]  T. Matthews Dilemma of neutralization resistance of HIV-1 field isolates and vaccine development. , 1994, AIDS research and human retroviruses.

[30]  A J Langlois,et al.  Principal neutralizing domain of the human immunodeficiency virus type 1 envelope protein. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[31]  J. Sodroski,et al.  Molecular cloning and analysis of functional envelope genes from human immunodeficiency virus type 1 sequence subtypes A through G. The WHO and NIAID Networks for HIV Isolation and Characterization , 1996, Journal of virology.

[32]  N. Sullivan,et al.  Characterization of neutralizing monoclonal antibodies to linear and conformation-dependent epitopes within the first and second variable domains of human immunodeficiency virus type 1 gp120 , 1993, Journal of virology.

[33]  J. Hildreth,et al.  HIV acquires functional adhesion receptors from host cells. , 1995, AIDS research and human retroviruses.

[34]  A. Trkola,et al.  Cross-clade neutralization of primary isolates of human immunodeficiency virus type 1 by human monoclonal antibodies and tetrameric CD4-IgG , 1995, Journal of virology.

[35]  D R Burton,et al.  Efficient neutralization of primary isolates of HIV-1 by a recombinant human monoclonal antibody. , 1994, Science.

[36]  J. Sodroski,et al.  Human anti-V2 monoclonal antibody that neutralizes primary but not laboratory isolates of human immunodeficiency virus type 1 , 1994, Journal of virology.

[37]  L. Sawyer,et al.  Neutralization sensitivity of human immunodeficiency virus type 1 is determined in part by the cell in which the virus is propagated , 1994, Journal of virology.

[38]  J. Moore,et al.  Quantitative analysis of serum neutralization of human immunodeficiency virus type 1 from subtypes A, B, C, D, E, F, and I: lack of direct correlation between neutralization serotypes and genetic subtypes and evidence for prevalent serum-dependent infectivity enhancement , 1996, Journal of virology.

[39]  M. Hilgartner,et al.  A human monoclonal antibody against the CD4-binding site of HIV1 gp120 exhibits potent, broadly neutralizing activity. , 1991, Research in virology.

[40]  A. Pinter,et al.  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. , 1993, AIDS research and human retroviruses.

[41]  M. Girard,et al.  A novel, glycan-dependent epitope in the V2 domain of human immunodeficiency virus type 1 gp120 is recognized by a highly potent, neutralizing chimpanzee monoclonal antibody , 1994, Journal of virology.

[42]  D. Ho,et al.  Identification and characterization of a neutralization site within the second variable region of human immunodeficiency virus type 1 gp120 , 1992, Journal of virology.

[43]  M. Schutten,et al.  Enhancement of Infectivity of a Non‐Syncytium Inducing HIV‐1 by sCD4 and by Human Antibodies that Neutralize Syncytium Inducing HIV‐1 , 1995, Scandinavian journal of immunology.

[44]  D. Markovitz,et al.  The role of mononuclear phagocytes in HTLV-III/LAV infection. , 1986, Science.

[45]  A. Pinter,et al.  Presentation of native epitopes in the V1/V2 and V3 regions of human immunodeficiency virus type 1 gp120 by fusion glycoproteins containing isolated gp120 domains , 1994, Journal of virology.

[46]  A. Trkola,et al.  Cross-neutralizing activity against divergent human immunodeficiency virus type 1 isolates induced by the gp41 sequence ELDKWAS , 1994, Journal of virology.

[47]  D. Ho,et al.  Another discontinuous epitope on glycoprotein gp120 that is important in human immunodeficiency virus type 1 neutralization is identified by a monoclonal antibody. , 1991, Proceedings of the National Academy of Sciences of the United States of America.