An MPER antibody neutralizes HIV-1 using germline features shared among donors

Area of Science:

• Immunology
• Virology
• Structural Biology

Background:

• The membrane-proximal external region (MPER) of HIV-1 envelope glycoprotein (Env) is a key target for broadly neutralizing antibodies.
• Existing MPER antibodies often possess specific characteristics like long CDRH3s, reduced germline precursor activity, and belong to the IgG3 subclass.

Purpose of the Study:

• To describe a novel broadly neutralizing antibody, PGZL1, targeting the HIV-1 MPER.
• To characterize PGZL1's genetic and structural features, comparing it to other MPER antibodies like 4E10.
• To investigate the mechanism of MPER recognition and viral membrane interaction.

Main Methods:

• Characterization of antibody PGZL1, including its genetic origins (V/D-region genes) and subclass (IgG1).
• Assessment of PGZL1's neutralization breadth against a panel of HIV-1 isolates.
• Determination of crystal structures of lipid-bound PGZL1 variants and cryo-electron microscopy (cryo-EM) reconstruction of an Env-PGZL1 complex.

Main Results:

• PGZL1, an IgG1 MPER antibody, shares germline genes with 4E10 but has a shorter CDRH3 and reduced polyreactivity.
• A recombinant PGZL1 variant demonstrated pan-neutralization of 130 HIV-1 isolates.
• Structural studies revealed how PGZL1 recognizes the MPER and interacts with the viral membrane.

Conclusions:

• PGZL1 represents a distinct class of MPER broadly neutralizing antibodies within the major IgG1 subclass.
• Understanding the genetic and structural basis of PGZL1's activity provides insights into eliciting similar antibodies through immunogen design.
• These findings advance the development of effective HIV-1 vaccines targeting conserved viral epitopes.