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Characterization of conserved human immunodeficiency virus type 1 gp120 neutralization epitopes exposed upon gp120-CD4 binding.

Department of Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

ABSTRACT

Interaction with the CD4 receptor enhances the exposure on the human immunodeficiency type 1 gp120 exterior envelope glycoprotein of conserved, conformation-dependent epitopes recognized by the 17b and 48d neutralizing monoclonal antibodies. The 17b and 48d antibodies compete with anti-CD4 binding antibodies such as 15e or 21h, which recognize discontinuous gp120 sequences near the CD4 binding region. To characterize the 17b and 48d epitopes, a panel of human immunodeficiency virus type 1 gp120 mutants was tested for recognition by these antibodies in the absence or presence of soluble CD4. Single amino acid changes in five discontinuous, conserved, and generally hydrophobic regions of the gp120 glycoprotein resulted in decreased recognition and neutralization by the 17b and 48d antibodies. Some of these regions overlap those previously shown to be important for binding of the 15e and 21h antibodies or for CD4 binding. These results suggest that discontinuous, conserved epitopes proximal to the binding sites for both CD4 and anti-CD4 binding antibodies become better exposed upon CD4 binding and can serve as targets for neutralizing antibodies.

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• Mbah, H. A., Burda, S., Gorny, M. K., Williams, C., Revesz, K., Zolla-Pazner, S., Nyambi, P. N. (2001). Effect of Soluble CD4 on Exposure of Epitopes on Primary, Intact, Native Human Immunodeficiency Virus Type 1 Virions of Different Genetic Clades. J. Virol. 75: 7785-7788 [Abstract] [Full Text]  
• Moore, J. P., Parren, P. W. H. I., Burton, D. R. (2001). Genetic Subtypes, Humoral Immunity, and Human Immunodeficiency Virus Type 1 Vaccine Development. J. Virol. 75: 5721-5729 [Full Text]  
• Edwards, T. G., Hoffman, T. L., Baribaud, F., Wyss, S., LaBranche, C. C., Romano, J., Adkinson, J., Sharron, M., Hoxie, J. A., Doms, R. W. (2001). Relationships between CD4 Independence, Neutralization Sensitivity, and Exposure of a CD4-Induced Epitope in a Human Immunodeficiency Virus Type 1 Envelope Protein. J. Virol. 75: 5230-5239 [Abstract] [Full Text]  
• Si, Z., Cayabyab, M., Sodroski, J. (2001). Envelope Glycoprotein Determinants of Neutralization Resistance in a Simian-Human Immunodeficiency Virus (SHIV-HXBc2P 3.2) Derived by Passage in Monkeys. J. Virol. 75: 4208-4218 [Abstract] [Full Text]  
• Yonezawa, A., Hori, T., Takaori-Kondo, A., Morita, R., Uchiyama, T. (2001). Replacement of the V3 Region of gp120 with SDF-1 Preserves the Infectivity of T-Cell Line-Tropic Human Immunodeficiency Virus Type 1. J. Virol. 75: 4258-4267 [Abstract] [Full Text]  
• Martín, J., LaBranche, C. C., González-Scarano, F. (2001). Differential CD4/CCR5 Utilization, gp120 Conformation, and Neutralization Sensitivity between Envelopes from a Microglia-Adapted Human Immunodeficiency Virus Type 1 and Its Parental Isolate. J. Virol. 75: 3568-3580 [Abstract] [Full Text]  
• Singer, I. I., Scott, S., Kawka, D. W., Chin, J., Daugherty, B. L., DeMartino, J. A., DiSalvo, J., Gould, S. L., Lineberger, J. E., Malkowitz, L., Miller, M. D., Mitnaul, L., Siciliano, S. J., Staruch, M. J., Williams, H. R., Zweerink, H. J., Springer, M. S. (2001). CCR5, CXCR4, and CD4 Are Clustered and Closely Apposed on Microvilli of Human Macrophages and T Cells. J. Virol. 75: 3779-3790 [Abstract] [Full Text]  
• Means, R. E., Matthews, T., Hoxie, J. A., Malim, M. H., Kodama, T., Desrosiers, R. C. (2001). Ability of the V3 Loop of Simian Immunodeficiency Virus To Serve as a Target for Antibody-Mediated Neutralization: Correlation of Neutralization Sensitivity, Growth in Macrophages, and Decreased Dependence on CD4. J. Virol. 75: 3903-3915 [Abstract] [Full Text]  
• Kolchinsky, P., Kiprilov, E., Bartley, P., Rubinstein, R., Sodroski, J. (2001). Loss of a Single N-Linked Glycan Allows CD4-Independent Human Immunodeficiency Virus Type 1 Infection by Altering the Position of the gp120 V1/V2 Variable Loops. J. Virol. 75: 3435-3443 [Abstract] [Full Text]  
• York, J., Follis, K. E., Trahey, M., Nyambi, P. N., Zolla-Pazner, S., Nunberg, J. H. (2001). Antibody Binding and Neutralization of Primary and T-Cell Line-Adapted Isolates of Human Immunodeficiency Virus Type 1. J. Virol. 75: 2741-2752 [Abstract] [Full Text]  
• Mori, T., Boyd, M. R. (2001). Cyanovirin-N, a Potent Human Immunodeficiency Virus-Inactivating Protein, Blocks both CD4-Dependent and CD4-Independent Binding of Soluble gp120 (sgp120) to Target Cells, Inhibits sCD4-Induced Binding of sgp120 to Cell-Associated CXCR4, and Dissociates Bound sgp120 from Target Cells. Antimicrob. Agents Chemother. 45: 664-672 [Abstract] [Full Text]  
• Kolchinsky, P., Kiprilov, E., Sodroski, J. (2001). Increased Neutralization Sensitivity of CD4-Independent Human Immunodeficiency Virus Variants. J. Virol. 75: 2041-2050 [Abstract] [Full Text]  
• Yang, X., Wyatt, R., Sodroski, J. (2001). Improved Elicitation of Neutralizing Antibodies against Primary Human Immunodeficiency Viruses by Soluble Stabilized Envelope Glycoprotein Trimers. J. Virol. 75: 1165-1171 [Abstract] [Full Text]  
• Fouts, T. R., Tuskan, R., Godfrey, K., Reitz, M., Hone, D., Lewis, G. K., DeVico, A. L. (2000). Expression and Characterization of a Single-Chain Polypeptide Analogue of the Human Immunodeficiency Virus Type 1 gp120-CD4 Receptor Complex. J. Virol. 74: 11427-11436 [Abstract] [Full Text]  
• Ye, Y., Si, Z. H., Moore, J. P., Sodroski, J. (2000). Association of Structural Changes in the V2 and V3 Loops of the gp120 Envelope Glycoprotein with Acquisition of Neutralization Resistance in a Simian-Human Immunodeficiency Virus Passaged In Vivo. J. Virol. 74: 11955-11962 [Abstract] [Full Text]  
• Malenbaum, S. E., Yang, D., Cavacini, L., Posner, M., Robinson, J., Cheng-Mayer, C. (2000). The N-Terminal V3 Loop Glycan Modulates the Interaction of Clade A and B Human Immunodeficiency Virus Type 1 Envelopes with CD4 and Chemokine Receptors. J. Virol. 74: 11008-11016 [Abstract] [Full Text]  
• Salzwedel, K., Berger, E. A. (2000). Cooperative subunit interactions within the oligomeric envelope glycoprotein of HIV-1: Functional complementation of specific defects in gp120 and gp41. Proc. Natl. Acad. Sci. USA 10.1073/pnas.230438497v1 [Abstract] [Full Text]  
• Hoffman, T. L., Canziani, G., Jia, L., Rucker, J., Doms, R. W. (2000). A biosensor assay for studying ligand-membrane receptor interactions: Binding of antibodies and HIV-1 Env to chemokine receptors. Proc. Natl. Acad. Sci. USA 10.1073/pnas.190274097v1 [Abstract] [Full Text]  
• Edinger, A. L., Ahuja, M., Sung, T., Baxter, K. C., Haggarty, B., Doms, R. W., Hoxie, J. A. (2000). Characterization and Epitope Mapping of Neutralizing Monoclonal Antibodies Produced by Immunization with Oligomeric Simian Immunodeficiency Virus Envelope Protein. J. Virol. 74: 7922-7935 [Abstract] [Full Text]  
• Ly, A., Stamatatos, L. (2000). V2 Loop Glycosylation of the Human Immunodeficiency Virus Type 1 SF162 Envelope Facilitates Interaction of This Protein with CD4 and CCR5 Receptors and Protects the Virus from Neutralization by Anti-V3 Loop and Anti-CD4 Binding Site Antibodies. J. Virol. 74: 6769-6776 [Abstract] [Full Text]  
• Nyambi, P. N., Mbah, H. A., Burda, S., Williams, C., Gorny, M. K., Nádas, A., Zolla-Pazner, S. (2000). Conserved and Exposed Epitopes on Intact, Native, Primary Human Immunodeficiency Virus Type 1 Virions of Group M. J. Virol. 74: 7096-7107 [Abstract] [Full Text]  
• Glamann, J., Hirsch, V. M. (2000). Characterization of a Macaque Recombinant Monoclonal Antibody That Binds to a CD4-Induced Epitope and Neutralizes Simian Immunodeficiency Virus. J. Virol. 74: 7158-7163 [Abstract] [Full Text]  
• Myszka, D. G., Sweet, R. W., Hensley, P., Brigham-Burke, M., Kwong, P. D., Hendrickson, W. A., Wyatt, R., Sodroski, J., Doyle, M. L. (2000). Energetics of the HIV gp120-CD4 binding reaction. Proc. Natl. Acad. Sci. USA 97: 9026-9031 [Abstract] [Full Text]  
• Sanders, R. W., Schiffner, L., Master, A., Kajumo, F., Guo, Y., Dragic, T., Moore, J. P., Binley, J. M. (2000). Variable-Loop-Deleted Variants of the Human Immunodeficiency Virus Type 1 Envelope Glycoprotein Can Be Stabilized by an Intermolecular Disulfide Bond between the gp120 and gp41 Subunits. J. Virol. 74: 5091-5100 [Abstract] [Full Text]  
• Park, E. J., Gorny, M. K., Zolla-Pazner, S., Quinnan, G. V. Jr. (2000). A Global Neutralization Resistance Phenotype of Human Immunodeficiency Virus Type 1 Is Determined by Distinct Mechanisms Mediating Enhanced Infectivity and Conformational Change of the Envelope Complex. J. Virol. 74: 4183-4191 [Abstract] [Full Text]  
• Yamaguchi-Kabata, Y., Gojobori, T. (2000). Reevaluation of Amino Acid Variability of the Human Immunodeficiency Virus Type 1 gp120 Envelope Glycoprotein and Prediction of New Discontinuous Epitopes. J. Virol. 74: 4335-4350 [Abstract] [Full Text]