A new HIV-1 Rev structure optimizes interaction with target RNA (RRE) for nuclear export

Area of Science:

• Molecular Biology
• Virology
• Structural Biology

Background:

• HIV-1 Rev protein is essential for viral replication, mediating nuclear export of unspliced and partially-spliced viral transcripts.
• Rev assembly on the viral Rev response element (RRE) is critical for this process, but the mechanism remains unclear.
• The Rev assembly domain features a helical-hairpin structure with potential A-A, B-B, and C-C association interfaces.

Purpose of the Study:

• To determine the crystal structure of the HIV-1 Rev assembly domain.
• To elucidate the mechanism of Rev multimerization on the RRE.
• To identify potential targets for therapeutic intervention.

Main Methods:

• X-ray crystallography at 2.25 Å resolution.
• Structural analysis of the Rev assembly domain.
• Analysis of Rev-RRE interaction interfaces.

Main Results:

• A novel crystal structure of the Rev assembly domain was determined without mutations or chaperones.
• Observed B-B dimer arrangement is reversed compared to previous reports.
• The structure reveals tetramer formation via C-C interfaces and explains assembly of four Rev molecules on the RRE, with further addition through A-A interactions.

Conclusions:

• The determined Rev structure provides a mechanistic model for its assembly on the RRE, forming a specificity checkpoint.
• The Pro31-Trp45 axis at the C-C interface represents a potential target for antiviral drug development.
• Understanding Rev assembly is key to inhibiting HIV-1 replication.