Novel HIV-1 fusion peptide immunogens using glycan-engineered alphavirus-like particles

Area of Science:

• Vaccine development
• Virology
• Immunology

Background:

• Conserved epitopes are crucial targets for vaccines against diverse viruses like HIV-1.
• The HIV-1 fusion peptide (FP) is a small, promising target for vaccine development.
• Current vaccine strategies face challenges in eliciting effective immune responses against highly variable viruses.

Purpose of the Study:

• To develop novel immunogens targeting the HIV-1 fusion peptide (FP).
• To enhance FP-directed antibody titers and neutralizing capabilities.
• To evaluate the efficacy of engineered alphavirus-like particles (VLPs) as a vaccine platform.

Main Methods:

• Engineered three alphavirus-like particles (VLPs) displaying the HIV-1 FP.
• Introduced additional glycans to mask carrier-specific epitopes.
• Employed sequential immunization with heterologous carriers and diverse FP variants in guinea pig studies.
• Administered Env trimer boosting to assess neutralizing antibody responses.

Main Results:

• Sequential immunization with heterologous carriers enhanced FP-directed antibody titers.
• Glycan engineering further improved antibody responses.
• Using diverse FP variants with a common N-terminus increased neutralizing antibody titers.
• Combined strategies led to high FP-directed titers and FP-directed neutralizing antibodies against multi-clade HIV-1 in most animals.

Conclusions:

• Minimizing recurrent off-target epitopes across immunizations is critical for effective vaccine design.
• Engineered VLPs represent a promising platform for peptide-based immunizations.
• The developed strategy shows potential for generating broadly neutralizing antibodies against HIV-1.