A VRC13-like bNAb response is associated with complex escape pathways in HIV-1 envelope.

Area of Science:

• Immunology
• Virology
• Structural Biology

Background:

• Developing broadly neutralizing antibodies (bNAbs) is crucial for HIV-1 prevention and therapy.
• Understanding HIV-1 envelope (Env) evolution and antibody escape pathways is essential for rational immunogen design.
• The CD4-binding site (CD4bs) and V1V2 regions of Env are key targets for bNAbs.

Purpose of the Study:

• To characterize the viral evolutionary pathways leading to resistance against VRC13-like broadly neutralizing antibodies (bNAbs) in an HIV-1 infected individual.
• To identify specific mutations in HIV-1 Env gp120 that confer resistance to CD4bs-specific bNAbs, particularly VRC13.
• To inform the design of lineage-based immunogens aimed at eliciting VRC13-like bNAbs.

Main Methods:

• Longitudinal sequencing of autologous HIV-1 env genes from an individual with developing neutralization breadth.
• Pseudotyped virus neutralization assays to assess antibody resistance.
• Mapping of viral Env mutations and their impact on antibody binding and neutralization.

Main Results:

• An HIV-1 infected individual developed broad neutralization (>50% plasma neutralization breadth) targeting CD4bs and V1V2 regions.
• Viral evolution led to >2 log resistance against VRC13, a CD4bs-specific bNAb, primarily mediated by mutations in the CD4-binding loop (CD4BL).
• Complete VRC13 resistance required cooperative mutations within and adjacent to the CD4BL, including T359I, N363 to S362 substitution, and P369L, suggesting a complex escape mechanism.

Conclusions:

• HIV-1 Env exhibits complex evolution, developing resistance to VRC13-like bNAbs through cooperative mutations in the CD4BL.
• VRC13-class bNAbs may be refractory to rapid viral escape, making them promising candidates for therapeutic applications.
• Identification of viral intermediates and escape mutations provides insights for designing lineage-based immunogens to mature VRC13-like bNAb responses.