Improved Elicitation of Neutralizing Antibodies against Primary Human Immunodeficiency Viruses by Soluble Stabilized Envelope Glycoprotein Trimers

Abstract

Human immunodeficiency virus (HIV-1) envelope glycoprotein subunits, such as the gp120 exterior glycoprotein, typically elicit antibodies that neutralize T-cell-line-adapted (TCLA), but not primary, clinical isolates of HIV-1. Here we compare the immunogenicity of gp120 and soluble stabilized trimers, which were designed to resemble the functional envelope glycoprotein oligomers of primary and TCLA HIV-1 strains. For both primary and TCLA virus proteins, soluble stabilized trimers generated neutralizing antibody responses more efficiently than gp120 did. Trimers derived from a primary isolate elicited antibodies that neutralized primary and TCLA HIV-1 strains. By contrast, trimers derived from a TCLA isolate generated antibodies that neutralized only the homologous TCLA virus. Thus, soluble stabilized envelope glycoprotein trimers derived from primary HIV-1 isolates represent defined immunogens capable of eliciting neutralizing antibodies that are active against clinically relevant HIV-1 strains.

Llama Antibody Fragments with Cross-Subtype Human Immunodeficiency Virus Type 1 (HIV-1)-Neutralizing Properties and High Affinity for HIV-1 gp120

“…A12 was able to neutralize 59% of the subtype B viruses and 48% of the subtype C viruses included in the study on an IC 50 level, compared to 77% and 56% for the broadly neutralizing anti-CD4bs MAb b12. The difference in neutralization breadth between VHH A12 and MAb b12 was even more pronounced at an IC 90 level, indicating that VHH A12 is less broad in its cross-subtype neutralization ability than MAb b12. It should also be noted that MAb b12 was more reactive against the well-characterized subtype B and C reference panels of envelope pseudotyped viruses, which has been classified as suitable for tier 2 assessment of neutralizing antibodies.…”

“…It is possible that immunizing with an immunogen with better CD4-binding properties would result in more potent VHH. Previous studies have shown that purified trimeric envelope proteins are somewhat better at eliciting cross-subtype-neutralizing antibodies than monomeric recombinant gp120 (6,7,22,32,38,90). We are currently screening llamas immunized with recombinant trimeric gp140.…”

“…No virus inactivation was observed with a negative control VHH or with a pseudovirus bearing a rabies virus G-protein envelope (87). VHH and MAb b12 50% inhibitory concentration (IC 50 ) and IC 90 titers were calculated using the XLFit4 software (ID Business Solutions, Guildford, United Kingdom).…”

“…Virus neutralization was assayed in TZM-bl cells as described in the text. Shown is the percentage of viruses neutralized with an IC 50 and IC 90 of Յ50 g/ml. a VHH A12, D7, and C8 association rate constants (k a ), dissociation rate constants (k D ), and equilibrium dissociation constants (K D ϭ k D /k a ) for recombinant IIIB gp120 were determined in surface plasmon resonance studies.…”

Trimeric HIV-1 glycoprotein gp140 immunogens and native HIV-1 envelope glycoproteins display the same closed and open quaternary molecular architectures

“…Most studies that have compared the two forms using the same Env genotype have shown that gp140 trimers are superior to gp120 monomers at inducing neutralizing antibodies (19)(20)(21). However, the improvement in immunogenicity is not yet good enough to conclude that any forms of gp140 trimers, in their current iteration, are good enough to use in practical HIV-1 vaccines.…”