Initiation of HIV neutralizing B cell lineages with sequential envelope immunizations.

Area of Science:

• Immunology
• Vaccinology
• Virology

Background:

• HIV-1 vaccine development aims to mimic the evolution of broadly neutralizing antibodies (bnAbs) observed during natural infection.
• Understanding host tolerance mechanisms is crucial for designing effective vaccine strategies that overcome natural immune limitations.

Purpose of the Study:

• To investigate host tolerance mechanisms that restrict the development of CD4-binding site (CD4bs) bnAbs during sequential HIV-1 Env vaccination.
• To evaluate the neutralizing capacity and B cell receptor characteristics of vaccine-induced CD4bs antibodies.

Main Methods:

• Sequential vaccination with HIV-1 Env immunogens in macaques and Env-expressing B cell receptor knock-in mice.
• Analysis of B cell development, receptor editing, and antibody somatic mutation accumulation.
• Assessment of antibody neutralization breadth against HIV-1 strains and recognition of Env trimers.

Main Results:

• Sequential Env vaccination induced CD4bs antibodies in macaques with limited neutralization (7% of strains) and modest somatic mutations.
• In mice, naive CD4bs Env+ B cell clones became anergic or deleted, with some undergoing receptor editing to become Env-.
• Sequential Env immunization rescued anergic Env+ precursor B cells, unlike repetitive immunizations.

Conclusions:

• Stepwise immunization initiates CD4bs-bnAb responses, but host immune tolerance mechanisms significantly restrict their development.
• Future sequential immunogen-based vaccine regimens must incorporate strategies to expand bnAb precursor B cell pools to enhance efficacy.