Highly efficient neutralization of HIV with recombinant CD4-immunoglobulin molecules.
The human immunodeficiency virus type 1 (HIV-1) exploits the cell surface CD4 molecule to initiate the infection which can lead, eventually, to acquired immunodeficiency syndrome (AIDS). The HIV-1 envelope protein, gp120, interacts specifically with CD4 and soluble CD4 molecules have been shown to inhibit HIV infectivity in vitro. Effective inhibition in vivo may, however, require more potent reagents. We describe here the generation of molecules which combine the specificity of CD4 and the effector functions of different immunoglobulin subclasses. Replacing the VH and CH1 domains of either mouse gamma 2a or mu heavy chains with the first two N-terminal domains of CD4 results in molecules that are secreted in the absence of any immunoglobulin light chains. We find that the pentameric CD4-IgM chimaera is at least 1,000-fold more active than its dimeric CD4-IgG counterpart in syncytium inhibition assays and that effector functions, such as the binding of Fc receptors and the first component of the complement cascade (Clq), are retained. Similar chimaeric molecules, combining CD4 with human IgG were recently described by Capon et al., but these included the CH1 domain and did not bind Clq. Deletion of the CH1 domain may allow the association and secretion of heavy chains in the absence of light chains, and we suggest that the basic design of our constructs may be generally and usefully applied.
Traunecker
A
A
Basel Institute for Immunology, Switzerland.
Schneider
J
J
Kiefer
H
H
Karjalainen
K
K
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy; D000818:Animals; D000998:Antiviral Agents; D003166:Complement Activating Enzymes / Q000378:metabolism; D003172:Complement C1 / Q000378:metabolism; D015922:Complement C1q; D015699:HIV Envelope Protein gp120; D015497:HIV-1 / Q000187:drug effects*; D007127:Immunoglobulin Constant Regions; D007074:Immunoglobulin G / Q000502:physiology; D007075:Immunoglobulin M / Q000502:physiology; D007135:Immunoglobulin Variable Region; D007142:Immunoglobulin gamma-Chains; D007148:Immunoglobulin mu-Chains; D007136:Immunoglobulins / Q000502:physiology*; D046911:Macromolecular Substances; D051379:Mice; D010957:Plasmids; D011961:Receptors, Fc / Q000378:metabolism; D015728:Receptors, HIV; D011991:Receptors, Virus / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology*; D012191:Retroviridae Proteins / Q000276:immunology
D000998:Antiviral Agents; D003172:Complement C1; D015699:HIV Envelope Protein gp120; D007127:Immunoglobulin Constant Regions; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D007142:Immunoglobulin gamma-Chains; D007148:Immunoglobulin mu-Chains; D007136:Immunoglobulins; D046911:Macromolecular Substances; D011961:Receptors, Fc; D015728:Receptors, HIV; D011991:Receptors, Virus; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D012191:Retroviridae Proteins; D015922:Complement C1q; D003166:Complement Activating Enzymes