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

Abstract

The structure, replicative properties, and sensitivity to neutralization by soluble CD4 and monoclonal antibodies were examined for molecularly cloned envelope glycoproteins derived from human immunodeficiency virus type 1 (HIV-1) viruses either isolated directly from patients or passaged in T-cell lines. Complementation of virus entry into peripheral blood mononuclear cell targets by primary patient envelope glycoproteins exhibited efficiencies ranging from that observed for the HXBc2 envelope glycoproteins, which are derived from a T-cell line-passaged virus, to approximately fivefold-lower values. The ability of the envelope glycoproteins to complement virus entry roughly correlated with sensitivity to neutralization by soluble CD4. Laboratory-adapted viruses were sensitive to neutralization by monoclonal antibodies directed against the CD4-binding site and the third variable (V3) loop of the gp120 glycoprotein. By comparison, viruses with envelope glycoproteins from primary patient isolates exhibited decreased sensitivity to neutralization by these monoclonal antibodies; for these viruses, neutralization sensitivity correlated with replicative ability. Subinhibitory concentrations of soluble CD4 and a CD4-binding site-directed antibody significantly enhanced the entry of viruses containing envelope glycoproteins from some primary patient isolates. The sensitivity of viruses containing the different envelope glycoproteins to neutralization by soluble CD4 or monoclonal antibodies could be predicted by assays dependent on the binding of the inhibitory molecule to the oligomeric envelope glycoprotein complex but less well by assays measuring binding to the monomeric gp120 glycoprotein. These results indicate that the intrinsic structure of the oligomeric envelope glycoprotein complex of primary HIV-1 isolates, while often less than optimal with respect to the mediation of early events in virus replication, allows a relative degree of resistance to neutralizing antibodies. The interplay of selective forces for higher virus replication efficiency and resistance to neutralizing antibodies could explain the temporal course described for the in vivo emergence of HIV-1 isolates with differing phenotypes.

The Envelope Glycoprotein Ectodomains Determine the Efficiency of CD4+ T Lymphocyte Depletion in Simian– Human Immunodeficiency Virus–Infected Macaques

“…Plasmids Expressing Envelope Glycoproteins. The pSVIIIenv plasmid expressing the HIV-1 89.6 envelope glycoproteins has been described elsewhere (40). An envelope expressor plasmid, designated pSVIIIenv-89.6tail, containing the modified COOH terminus of the KB9 gp41 envelope glycoprotein, was constructed using the BamHI-NcoI (blunted) fragment of KB9 cloned into the BamHI-XhoI (blunted)-digested pSVIIIenv-89.6 plasmid.…”

Vaccine-induced enhancement of viral infections

“…Enhancement independent of FcR and CR may also occur. Neutralizing antibodies, but also soluble CD4, can enhance NSI/R5 virus infectivity [55,56] by inducing conformational changes in the viral envelope [57,58] and bringing the envelope in proximity of the CCR-5 co-receptor.…”

The antiviral activity of antibodies in vitro and in vivo

“…Possible differences in spike density between neutralization-sensitive TCLA strains of HIV-1 (low active spike densities) and neutralization-resistant primary isolates (high active spike densities) are quoted as an important factor in neutralization resistance (Klasse and Moore, 1996). Differences in spike densities between TCLA strains and primary isolates, however, are controversial (Karlsson et al, 1996;Sullivan et al, 1995). Alternatively, the resistance may be due to the poor accessibility of epitopes on the primary isolate envelope spike .…”