Antiviral effects of different CD4-immunoglobulin constructs against HIV-1 and SIV: immunological characterization, pharmacokinetic data and in vivo experiments.
The CD4 cell surface antigen belongs to the immunoglobulin superfamily and is the primary receptor for the human immunodeficiency virus 1 (HIV-1). The high affinity interaction between HIV-1 and CD4 is mediated by the viral envelope glycoprotein gp120. Recombinant soluble CD4 (rsCD4) has been shown in vitro to be an effective inhibitor of HIV-1 and HIV-2 propagation in lymphoid cells. A variety of antibody-like molecules were constructed, consisting of different parts of the extracellular domain of CD4 fused to immunoglobulin constant regions. The fusion proteins were expressed in mammalian cell lines and purified via affinity chromatography. The specificity and anti-viral effects of the different CD4-immunoglobulin constructs against HIV were analysed by different immunological tests, i.e., immunofluorescence, neutralisation and in vitro assays. In pharmacokinetic studies, differences were found in serum half-life between the four- and two-domain CD4 constructs in cynomolgus monkeys and between glycosylated and deglycosylated CD4-Fc constructs in rabbits. In two in vivo experiments using the four-domain CD4-Fc in SIV-infected macaques, no beneficial effects were observed.
Langner
K D
KD
Forschungslabor der Behringwerke AG, Marburg, Federal Republic of Germany.
Niedrig
M
M
Fultz
P
P
Anderson
D
D
Reiner
G
G
Repke
H
H
Gelderblom
H
H
Seed
B
B
Hilfenhaus
J
J
Zettlmeissl
G
G
D000818:Animals; D000998:Antiviral Agents / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology; D001835:Body Weight; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D015699:HIV Envelope Protein gp120 / Q000378:metabolism / Q000648:ultrastructure; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology / Q000648:ultrastructure; D006207:Half-Life; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008253:Macaca mulatta; D008657:Metabolic Clearance Rate; D016253:Microscopy, Immunoelectron; D011993:Recombinant Fusion Proteins / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000628:therapy*; D015302:Simian Immunodeficiency Virus / Q000187:drug effects* / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology*; D013997:Time Factors; D014771:Virion / Q000187:drug effects / Q000276:immunology / Q000648:ultrastructure
D000998:Antiviral Agents; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins