Soluble HIV-1 Envelope Immunogens Derived from an Elite Neutralizer Elicit Cross-Reactive V1V2 Antibodies and Low Potency Neutralizing Antibodies

Abstract

We evaluated four gp140 Envelope protein vaccine immunogens that were derived from an elite neutralizer, subject VC10042, whose plasma was able to potently neutralize a wide array of genetically distinct HIV-1 isolates. We sought to determine whether soluble Envelope proteins derived from the viruses circulating in VC10042 could be used as immunogens to elicit similar neutralizing antibody responses by vaccination. Each gp140 was tested in its trimeric and monomeric forms, and we evaluated two gp140 trimer vaccine regimens in which adjuvant was supplied at all four immunizations or at only the first two immunizations. Interestingly, all four Envelope immunogens elicited high titers of cross-reactive antibodies that recognize the variable regions V1V2 and are potentially similar to antibodies linked with a reduced risk of HIV-1 acquisition in the RV144 vaccine trial. Two of the four immunogens elicited neutralizing antibody responses that neutralized a wide array of HIV-1 isolates from across genetic clades, but those responses were of very low potency. There were no significant differences in the responses elicited by trimers or monomers, nor was there a significant difference between the two adjuvant regimens. Our study identified two promising Envelope immunogens that elicited anti-V1V2 antibodies and broad, but low potency, neutralizing antibody responses.

Envelope Variants Circulating as Initial Neutralization Breadth Developed in Two HIV-Infected Subjects Stimulate Multiclade Neutralizing Antibodies in Rabbits

“…Only tier 1A viruses were neutralized at moderate to high levels, and similar to previous vaccine studies (12,17,19,35,36,48), almost no autologous neutralization was elicited (data not shown). This lack of autologous neutralization and limited heterologous neutralization compared to the moderate cross-clade neutralization breadth in the infected VC10014 and VC20013 subjects could be explained by several factors.…”

“…Other vaccine studies in guinea pigs or rabbits comparing Envs derived from elite neutralizers, T/F sequences, and consensus Envs have resulted in similar, modest neutralization potency and breadth against panels of viruses and significant variation in individual animals (17,19). These studies, as well as our prior vaccine studies using sequentially derived Envs (47,48), have contributed to an appreciation of the antigenic properties of Env components and how combinations of Envs can be used, but there are still no clearly superior sequences that have been identified.…”

“…Thus, a high degree of research effort has been devoted to understanding the development of NAbs in HIV infection (8)(9)(10) in order to inform development of an Env-based vaccine to elicit a broad cross-clade neutralizing response in animal models (7,11). Unfortunately, NAbs elicited by vaccination so far have shown weak to moderate potency and a low degree of neutralization breadth, despite the use of diverse envelopes (Envs) in the vaccines tested (12)(13)(14)(15)(16)(17)(18)(19) and novel approaches to develop re-combinant Env proteins that mimic the native trimeric Env protein (20). In addition, Envs isolated from different human subjects have divergent antigenic and immunogenic properties (11), further complicating the selection criteria for candidate immunogens.…”

Induction of Heterologous Tier 2 HIV-1-Neutralizing and Cross-Reactive V1/V2-Specific Antibodies in Rabbits by Prime-Boost Immunization

“…Bioplex assays against peptides were performed as previously described (36). Briefly, 15-mer peptides overlapping by 11-mers corresponding to the variable regions 1 to 3 (V1 to V3) or conserved region 1 or 5 (C1 or C5, respectively) were obtained through the HIV-1 Consensus Subtype B Env Peptide Set from the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH.…”

Immunization of Mice with Live-Attenuated Late Liver Stage-Arresting Plasmodium yoelii Parasites Generates Protective Antibody Responses to Preerythrocytic Stages of Malaria

“…PyCSP (amino acids [aa] 21 to 362) was cloned into the pTT3 vector under the control of the cytomegalovirus (CMV) promoter (36). This plasmid was transfected into HEK293F cells as described previously (37) and purified by chromatography using a HisTrapp-FF nickel affinity column (GE Healthcare, Pittsburgh, PA) followed by a HiLoad 16/60 Superdex 200 size exclusion column (GE Healthcare, Pittsburgh, PA). Fractions containing monomeric PyCSP were collected, concentrated for final storage in phosphate-buffered saline (PBS) (pH 7.4), and analyzed by native PAGE and SDS-PAGE for size and purity.…”