High concentrations of recombinant soluble CD4 are required to neutralize primary human immunodeficiency virus type 1 isolates.
There is substantial evidence supporting the CD4 molecule as the principal cellular receptor for the human immunodeficiency virus type 1 (HIV-1). A number of truncated recombinant soluble CD4 (sCD4) molecules have been produced and shown to easily neutralize infection of laboratory strains of HIV-1 in vitro, and clinical trials using these sCD4 preparations have begun in patients with AIDS. Infectious HIV-1 titers in the plasma and peripheral blood mononuclear cells of five patients receiving sCD4 at 30 mg/day were sequentially monitored. No significant decrease in viral titers was found during therapy. Furthermore, plasma samples from eight patients with AIDS were titrated for HIV-1 with and without the addition of sCD4 ex vivo. Despite the addition of sCD4 at up to 1 mg/ml, there was little change in plasma viral titers. Subsequently, 10 primary HIV-1 isolates were tested for their susceptibility to neutralization in vitro by one preparation of sCD4. Neutralization of these clinical isolates required 200-2700 times more sCD4 than was needed to inhibit laboratory strains of HIV-1. Similar results were observed using one other monomeric sCD4 preparation and two multimeric CD4-immunoglobulin hybrid molecules. We conclude that unlike laboratory strains, primary HIV-1 isolates require high concentrations of sCD4 for neutralization. This phenomenon may pose a formidable problem for sCD4-based therapeutics in the treatment of HIV-1 infection.
Daar
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Department of Medicine, Cedars-Sinai Medical Center, University of California, Los Angeles School of Medicine 90048.
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Moudgil
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D000386:AIDS-Related Complex / Q000276:immunology / Q000628:therapy*; D000163:Acquired Immunodeficiency Syndrome / Q000382:microbiology / Q000628:therapy*; D015704:CD4 Antigens / Q000008:administration & dosage / Q000276:immunology*; D004341:Drug Evaluation; D015497:HIV-1 / Q000276:immunology* / Q000302:isolation & purification; D006801:Humans; D009500:Neutralization Tests; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology
D015704:CD4 Antigens; D011994:Recombinant Proteins