Resistance of primary isolates of human immunodeficiency virus type 1 to soluble CD4 is independent of CD4-rgp120 binding affinity.

Abstract

The infection of human cells by laboratory strains of human immunodeficiency virus type 1 (HIV-1) can be blocked readily in vitro by recombinant soluble CD4 and CD4-immunoglobulin hybrid molecules. In contrast, infection by primary isolates of HIV-1 is much less sensitive to blocking in vitro by soluble CD4-based molecules. To investigate the molecular basis for this difference between HIV-1 strains, we isolated the gpl20-encoding genes from several CD4-resistant and CD4-sensitive HIV-1 strains and characterized the CD4-bind_ properties of their recombinant gpl20 (rgpl2O) products. Extensive amino acid sequence variation was found between the gpl20 genes of CD4-resistant and CD4-sensitive HIV-1 isolates. However, the CD4-binding affinities of rgpl20 from strains with markedly different CD4 sensitivities were essentially the same, and only small differences were observed in the kinetics of CD4 binding. These results suggest that the lower sensitivity of primary HIV-1 isolates to neutralization by CD4-based molecules is not due to lower binding affinity between soluble CD4 and free gpl20.

Biochemical and Biological Characterization of a Dodecameric CD4-Ig Fusion Protein

“…The differential capacity of sCD4 to neutralize tissue culture laboratory-adapted strains versus many primary isolates is striking. In the initial report describing this difference, Ho and colleagues (13) found that the concentrations of sCD4 required to neutralize primary isolates in vitro were up to 1000-fold higher than those required to neutralize tissue culture laboratory-adapted strains.…”

Biological consequences of human immunodeficiency virus type 1 envelope polymorphism: does variation matter?: 1995 Fleming Lecture Delivered at the 134th Meeting of the Society for General Microbiology, 26 March 1996

“…Several reports considering the resistance of primary viruses to neutralization by sCD4 have proposed that this is due to a reduced affinity of the envelope for CD4, apparent in the oligomeric form of the glycoprotein, but not in the monomer (Ashkenazi et al, 1991;Turner et al, 1992). However, this conclusion was based on the failure to demonstrate differences in the affinities of monomeric gp120 proteins from primary and laboratory cultured viruses for sCD4 (Turner et al,, 1992).…”

“…relating to primary virus glycoprotein function have studied single proteins, with the implicit assumption that a single clone would be representative of the virus population (Ashkenazi et al, 1991;Daar & Ho, 1991;Turner et al, 1992). In order to address the characteristics of primary virus populations and their interactions with CD4 and neutralizing antibodies, we have studied multiple gpI20 glycoproteins derived from several primary isolates.…”

Rapid Prescreening for Antiviral Agents against HIV-1 Based on Their Inhibitory Activity in Site-Directed Immunoassays. Approaches Applicable to Epidemic HIV-1 Strains

“…The observation that many primary HIV-1 isolates are resistant to the antiviral effect of soluble CD4, the cell receptor for HIV-1, unlike laboratory strains of the virus (Ashkenazi et al, 1991;Brighty et al, 1991;Moore et a/., 1992;Turner et al, 1992) suggests the importance of including primary HIV-1 isolates belonging to distinct HIV-1 families (Sternberg, 1992) into any investigation concerning antiviral compounds before considering their application for antiviral chemotherapy and designing clinical trials. Such caution is further justified by the observation that several compounds having antiviral activity against HIV-1 IIIB (Neurath et a/., 1991) were inactive against HIV-1 MN (fable 1).…”