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

Abstract

Two assays for measuring inhibition of human immunodeficiency virus type 1 (HIV-1) infection by soluble CD4 (sCD4) are described. Experiments in which sCD4, HIV-1, and cell concentrations and sequence of combination, noninfectious/infectious particle ratio, and temperature were varied produced results that support the conclusion that sCD4 inhibits HIV-1 infection by two mechanisms: reversible blockage of receptor binding and irreversible inactivation of infectivity. Fresh isolates obtained from HIV-1-infected persons were tested in both assays and found to be more resistant to both mechanisms of sCD4-mediated inhibition than multiply passaged laboratory strains. Binding studies revealed similar affinities for sCD4 in detergent lysates of sensitive and resistant strains at both 4 and 37°C. The avidity of intact virions for sCD4 was lower at 4 than at 37°C, and in the presence of excess sCD4, less sCD4 was bound at 4 than at 37°C. The avidity differences were similar for fresh isolates and laboratory strains. However, fresh isolates were more resistant to sCD4-induced shedding of envelope * Corresponding author.

Macrophage-tropic and T-cell line-adapted chimeric strains of human immunodeficiency virus type 1 differ in their susceptibilities to neutralization by soluble CD4 at different temperatures

“…An interpretation of these data is that the reaction between cell-surface CD4 and the envelope glycoprotein complex of primary viruses is relatively inefficient and rate limiting for infection. This would be consistent with prior results obtained from studies of the interactions of sCD4 with primary viruses (18,21,26,33).…”

“…We suggest that what we have observed in this study with molecularly cloned viruses, and previously with uncloned primary and T-cell line-adapted viruses (18,28), reflects functional differences between the envelope glycoproteins of macrophage-tropic, primary HIV-1 viruses and those adapted to growth in T-cell lines (15). It has been known for several years that primary HIV-1 isolates grown only in PBMC, or plasma virus ex vivo, resist neutralization by sCD4, in contrast to viruses adapted to growth in transformed T-cell lines (3,4,7,18,21,26,33). All primary viruses we have tested shed gpl20 more rapidly at 4°C than at 37°C.…”

“…The resistance of primary viruses to neutralization by sCD4 is not due to an intrinsic inability of their gpl20 molecules to bind sCD4 (3,4,21,30). However, intact virions of primary viruses show reduced binding of sCD4 compared with that of virions of T-cell line-adapted viruses (21,26), probably because of a decrease in the rate of sCD4 binding (18). Curiously, at least some primary viruses become sensitive to sCD4 after prolonged incubation with this agent at 4°C but not at 37°C (18,21).…”

Replicative function and neutralization sensitivity of envelope glycoproteins from primary and T-cell line-passaged human immunodeficiency virus type 1 isolates

“…The interaction of the envelope glycoproteins of different HIV-1 isolates with the CD4 viral receptor appears to differ, since primary viruses are resistant to a soluble form of CD4 (sCD4), in contrast to laboratory-passaged isolates (18,28). Differences in the affinity of sCD4, apparent only in the context of the oligomeric envelope glycoproteins, for primary and laboratory-passaged HIV-1 isolates have been suggested as an explanation of this relative resistance (5,32,39,41,45,58,60).…”

Molecular decoys: antidotes, therapeutics and immunomodulators

“…Despite the optimism, however, it turned out that CD4based decoys simply did not have the clout required to keep HIV in check. It was quickly realized that the neutralizing potency of sCD4 was preferentially greater for lab adapted strains of HIV than for the field isolates of this virus [28,29]. The mechanism for neutralization by the decoy required induced gp120 shedding that turned out to be much more demanding for the field isolates [30].…”