Mechanistic insights into lenacapavir-induced off-pathway HIV-1 capsid assembly

Area of Science:

• Structural biology
• Virology
• Computational biophysics

Background:

• The human immunodeficiency virus type 1 (HIV-1) capsid is a protein shell essential for viral replication.
• Capsid protein (CA) subunits assemble into a cone-like structure, crucial for genome packaging and nuclear entry.
• Inositol hexakisphosphate (IP6) is a cellular molecule that promotes proper capsid assembly.

Purpose of the Study:

• To elucidate the mechanism by which the long-acting HIV-1 inhibitor Lenacapavir (LEN) disrupts capsid assembly.
• To investigate the interplay between LEN, IP6, and capsid protein (CA) interactions.
• To understand how LEN affects HIV-1 morphogenesis and viral maturation.

Main Methods:

• Coarse-grained molecular dynamics simulations were employed to model HIV-1 capsid assembly.
• A ribonucleoprotein model was incorporated to simulate genome packaging.
• The effects of LEN and IP6 on CA subunit interactions and lattice formation were analyzed.

Main Results:

• LEN accelerates hexamer formation but inhibits pentamer incorporation, leading to malformed, incomplete capsids.
• LEN-treated capsids showed impaired RNA encapsulation, indicating defective maturation.
• Simulations confirmed LEN disrupts the formation of high-curvature lattice regions necessary for capsid closure.

Conclusions:

• Lenacapavir (LEN) perturbs HIV-1 capsid assembly by inducing off-pathway structures, thereby inhibiting viral maturation.
• The findings reveal the molecular mechanism of LEN's action, highlighting its potential as an antiviral therapeutic.
• This study provides insights into targeting large, self-assembling protein complexes like the HIV-1 capsid.