HIV-1-based Virus-like Particles that Morphologically Resemble Mature, Infectious HIV-1 Virions

A prophylactic vaccine eliciting both broad neutralizing antibodies (bNAbs) to the HIV-1 envelope glycoprotein (Env) and strong T cell responses would be optimal for preventing HIV-1 transmissions. Replication incompetent HIV-1 virus-like particles (VLPs) offer the opportunity to present authentic-s...

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Bibliographic Details
Published in:Viruses 2019-06, Vol.11 (6), p.507
Main Authors: Gonelli, Christopher A, Khoury, Georges, Center, Rob J, Purcell, Damian F J
Format: Article
Language:English
Subjects:
Acquired immune deficiency syndrome
AIDS
Antigens
Chromatography
Deoxyribonucleic acid
DNA
DNA vaccines
Enzymes
Epidemics
Expression vectors
Gag protein
Genomes
HIV
HIV-1
Human immunodeficiency virus
Lymphocytes T
mature-form
Morphology
Mutation
Packaging
particle assembly
Phenotypes
Plasmids
Polyclonal antibodies
Proteinase
Proteins
Recovery of function
RNA-directed DNA polymerase
Vaccines
Viral infections
Virions
virus-like particle
Virus-like particles
VLP
Vpr protein
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Summary:A prophylactic vaccine eliciting both broad neutralizing antibodies (bNAbs) to the HIV-1 envelope glycoprotein (Env) and strong T cell responses would be optimal for preventing HIV-1 transmissions. Replication incompetent HIV-1 virus-like particles (VLPs) offer the opportunity to present authentic-structured, virion-associated Env to elicit bNAbs, and also stimulate T cell responses. Here, we optimize our DNA vaccine plasmids as VLP expression vectors for efficient Env incorporation and budding. The original vector that was used in human trials inefficiently produced VLPs, but maximized safety by inactivating RNA genome packaging, enzyme functions that are required for integration into the host genome, and deleting accessory proteins Vif, Vpr, and Nef. These original DNA vaccine vectors generated VLPs with incomplete protease-mediated cleavage of Gag and were irregularly sized. Mutations to restore function within the defective genes revealed that several of the reverse transcriptase (RT) deletions mediated this immature phenotype. Here, we made efficient budding, protease-processed, and mature-form VLPs that resembled infectious virions by introducing alternative mutations that completely removed the RT domain, but preserved most other safety mutations. These VLPs, either expressed from DNA vectors in vivo or purified after expression in vitro, are potentially useful immunogens that can be used to elicit antibody responses that target Env on fully infectious HIV-1 virions.
ISSN:1999-4915
1999-4915
DOI:10.3390/v11060507