Immunogenicity and Protective Efficacy of Oligomeric Human Immunodeficiency Virus Type 1 gp140

Abstract

The biologically active form of the human immunodeficiency virus type 1 (HIV-1) envelope (Env) glycoprotein is oligomeric. We previously described a soluble HIV-1 IIIB Env protein, gp140, with a stable oligomeric structure composed of uncleaved gp120 linked to the ectodomain of gp41 (P. L. Earl, C. C. Broder, D. Long, S. A. Lee, J. Peterson, S. Chakrabarti, R. W. Doms, and B. Moss, J. Virol. 68:3015-3026, 1994). Here we compared the antibody responses of rabbits to gp120 and gp140 that had been produced and purified in an identical manner. The gp140 antisera exhibited enhanced cross-reactivity with heterologous Env proteins as well as greater neutralization of HIV-1 compared to the gp120 antisera. To examine both immunogenicity and protective efficacy, we immunized rhesus macaques with oligomeric gp140. Strong neutralizing antibodies against a homologous virus and modest neutralization of heterologous laboratory-adapted isolates were elicited. No neutralization of primary isolates was observed. However, a substantial fraction of the neutralizing activity could not be blocked by a V3 loop peptide. After intravenous challenge with simian-HIV virus SHIV-HXB2, three of the four vaccinated macaques exhibited no evidence of virus replication.

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

“…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.…”

Adjuvant-enhanced antibody responses to recombinant proteins correlates with protection of mice and monkeys to orthopoxvirus challenges

“…Therefore, we anticipated that antibodies to these VACV proteins would cross react with the MPXV homologs and provide at least partial protection. We chose to use QS-21, based on our previous experience with recombinant HIV proteins in a monkey model [62], even though we had not yet determined the superiority of this adjuvant for inducing VACV protection in mice. The recombinant VACV proteins were immunogenic in monkeys and binding antibodies were detected after the first immunization and boosted by a second, at which time VACV neutralizing and comet-reducing antibodies were also found.…”

Role of Neutralizing Antibodies in Protective Immunity Against HIV

“…Several approaches have been tried with reasonable success. 88,[155][156][157][158][159][160][161][162][163][164][165][166] Yang and colleagues used GCN4-stabilized oligomers to demonstrate that antibodies induced by oligomeric gp140 were more effective at neutralizing heterologous primary isolates, compared to antibodies elicited by the corresponding monomeric gp120 protein. 167 Earl and colleagues made similar observations in rhesus macaques using a trimeric Env protein from SIV.…”