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.
Highlights
Vaccination with live attenuated viruses has been a highly successful public health intervention as exemplified by the control of poliomyelitis and eradication of smallpox, both of which previously caused substantial mortality and morbidity globally
This paper describes the immunogenicity of these mature-form VLPs (mVLPs) to immature (Gag-only core) virus-like particles (VLPs), as well as the introduction of modifications to enhance incorporation and stabilization of envelope glycoprotein (Env) on mVLPs
The AD8 Env TM and cytoplasmic tail (CT) were replaced with the 93TH253.3 strain env TM/CT sequences, given the mVLP Gag was derived from this strain (AE-TMCT)
Summary
Vaccination with live attenuated viruses has been a highly successful public health intervention as exemplified by the control of poliomyelitis and eradication of smallpox, both of which previously caused substantial mortality and morbidity globally. A similar vaccine strategy for human immunodeficiency virus (HIV-1) is not feasible given its highly error-prone replication cycle and ability to form recombinant genomic sequences that collectively facilitate reversion to pathogenic virus. For this reason, much research has been conducted into developing subunit vaccines using components of the virus, the viral envelope glycoprotein (Env), which can elicit neutralizing antibodies capable of preventing HIV-1 infection [1,2]. Virus-like particle (VLP) immunogens have the advantage over conventional recombinant protein vaccines of larger size and repetitive display of antigenic epitopes, and are better at stimulating the innate and adaptive arms of the immune system [16,17,18,19]
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