High concentrations of recombinant soluble CD4 are required to neutralize primary human immunodeficiency virus type 1 isolates.
AUTOR(ES)
Daar, E S
RESUMO
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.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=54579Documentos Relacionados
- Envelope proteins from clinical isolates of human immunodeficiency virus type 1 that are refractory to neutralization by soluble CD4 possess high affinity for the CD4 receptor.
- Virions of primary human immunodeficiency virus type 1 isolates resistant to soluble CD4 (sCD4) neutralization differ in sCD4 binding and glycoprotein gp120 retention from sCD4-sensitive isolates.
- Resistance of primary isolates of human immunodeficiency virus type 1 to soluble CD4 is independent of CD4-rgp120 binding affinity
- Resistance of primary isolates of human immunodeficiency virus type 1 to soluble CD4 is independent of CD4-rgp120 binding affinity.
- Two mechanisms of soluble CD4 (sCD4)-mediated inhibition of human immunodeficiency virus type 1 (HIV-1) infectivity and their relation to primary HIV-1 isolates with reduced sensitivity to sCD4.