Reverse transcription progression and genome length regulate HIV-1 core elasticity and disassembly

Area of Science:

• Structural biology
• Virology
• Biophysics

Background:

• The structural and mechanical properties of the Human Immunodeficiency Virus type 1 (HIV-1) core are crucial for infection.
• Core elasticity plays a role in nuclear entry, but its molecular regulators are not well understood.
• Understanding core mechanics is key to developing antiviral strategies targeting viral entry and replication.

Purpose of the Study:

• To investigate the relationship between reverse transcription, genome length, HIV-1 core elasticity, and disassembly.
• To elucidate the molecular determinants governing HIV-1 core mechanical properties during early infection stages.

Main Methods:

• Atomic force microscopy (AFM) was employed to measure the elasticity of HIV-1 cores.
• Cores were analyzed at different stages of reverse transcription and with varying genome lengths.
• An RNase H-deficient HIV-1 mutant was used to assess the role of RNase H activity.

Main Results:

• Reverse transcription progressively reduces HIV-1 core elasticity, leading to increased brittleness as DNA synthesis advances.
• Shorter viral genomes correlated with higher elasticity, while longer genomes showed increased brittleness and disassembly.
• HIV-1 cores from RNase H-deficient mutants maintained high elasticity, indicating RNase H's role in destabilization.

Conclusions:

• Reverse transcription generates mechanical stress that facilitates viral core uncoating, a critical step for nuclear entry.
• Early reverse transcription preserves core elasticity, defining a temporal window for efficient nuclear import.
• Mechanical properties of the HIV-1 core are dynamically regulated by genome synthesis, impacting viral infectivity.