Immunogenicity of HIV-1-Based Virus-Like Particles with Increased Incorporation and Stability of Membrane-Bound Env

Abstract

An optimal prophylactic vaccine to prevent human immunodeficiency virus (HIV-1) transmission should elicit protective antibody responses against the HIV-1 envelope glycoprotein (Env). Replication-incompetent HIV-1 virus-like particles (VLPs) offer the opportunity to present virion-associated Env with a native-like structure during vaccination that closely resembles that encountered on infectious virus. Here, we optimized the incorporation of Env into previously designed mature-form VLPs (mVLPs) and assessed their immunogenicity in mice. The incorporation of Env into mVLPs was increased by replacing the Env transmembrane and cytoplasmic tail domains with those of influenza haemagglutinin (HA-TMCT). Furthermore, Env was stabilized on the VLP surface by introducing an interchain disulfide and proline substitution (SOSIP) mutations typically employed to stabilize soluble Env trimers. The resulting mVLPs efficiently presented neutralizing antibody epitopes while minimizing exposure of non-neutralizing antibody sites. Vaccination of mice with mVLPs elicited a broader range of Env-specific antibody isotypes than Env presented on immature VLPs or extracellular vesicles. The mVLPs bearing HA-TMCT-modified Env consistently induced anti-Env antibody responses that mediated modest neutralization activity. These mVLPs are potentially useful immunogens for eliciting neutralizing antibody responses that target native Env epitopes on infectious HIV-1 virions.

Expression, Purification, and Characterization of Bovine Leukemia Virus-Like Particles Produced in Drosophila S2 Cells

“…This conformational diversity also imposes significant barriers in the development of efficient vaccines aimed to induce broadly neutralizing antibodies, and several strategies have been proposed to stabilize Env trimers in the pre-fusion state (58)(59)(60)(61). Recently, Gonelli et al (62) generated VLPs displaying stabilized HIV Env trimers by introducing inter-subunit disulfides and a proline substitution (SOSIP) mutation. The resulting modified VLPs can efficiently activate B cells by displaying epitopes recognized by broadly neutralizing antibodies while minimizing exposure of nonneutralizing antibody sites (62).…”

“…Recently, Gonelli et al (62) generated VLPs displaying stabilized HIV Env trimers by introducing inter-subunit disulfides and a proline substitution (SOSIP) mutation. The resulting modified VLPs can efficiently activate B cells by displaying epitopes recognized by broadly neutralizing antibodies while minimizing exposure of nonneutralizing antibody sites (62).…”

Persistent immunogenicity of integrase defective lentiviral vectors delivering membrane-tethered native-like HIV-1 envelope trimers

“…Furthermore, VLPs with increased incorporation and stability of membrane-bound HIV-Env demonstrated superior immunogenicity than wild-type VLPs in mice 53 . Indeed, VLPs with increased density of Env are currently being pursued for vaccine development 55 , 56 . In our study we demonstrated that an IDLV expressing a membrane bound ConSOSL.UFO.750 induced higher IgG titers than an IDLV expressing the soluble ConSOSL.UFO.664, suggesting that expression of membrane-tethered Env trimers by IDLV is superior at activating B cells and inducing antigen specific antibodies compared to IDLV expressing soluble trimers.…”

Persistent Immunogenicity of Integrase Defective Lentiviral Vectors delivering membrane tethered Native-Like HIV-1 Envelope Trimers

“…For example, increasing the native-like Env trimer density on the surface of IDLV particles has the potential to increase Env recognition by immune cells and therefore results in more potent immune responses 51,52 . Indeed, VLPs with increased density of Env are currently being pursued for vaccine development 53,54 . By displaying viral antigens on a viral surface, VLPvaccines are strong inducers of Abs and helper T cell responses 55 .…”