Cell-free assays reveal that the HIV-1 capsid protects reverse transcripts from cGAS

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• The innate immune system uses cyclic GMP-AMP synthase (cGAS) to detect viral pathogens.
• cGAS recognizes reverse-transcribed DNA and initiates an antiviral response.
• The ability of Human Immunodeficiency Virus type 1 (HIV-1) to evade cGAS detection is not fully understood.

Purpose of the Study:

• To investigate how HIV-1 shields its genome from cGAS recognition.
• To elucidate the mechanisms underlying HIV-1 evasion of innate immune sensing.

Main Methods:

• Reconstitution of HIV-1 reverse transcription, genome release, and cGAS sensing in a cell-free system.
• Analysis of capsid stability under various conditions (thermal stress, mutations, inositol hexakisphosphate levels).
• Assessment of lenacapavir's effect on viral cores and cGAS activity in vitro and in cells.

Main Results:

• Wild-type HIV-1 capsids successfully protected viral DNA from cGAS recognition post-reverse transcription.
• Capsid destabilization via thermal stress, mutations, or reduced inositol hexakisphosphate (IP6) exposed viral DNA to cGAS.
• The capsid inhibitor lenacapavir disrupted HIV-1 cores, significantly enhancing cGAS activity.

Conclusions:

• The HIV-1 capsid lattice effectively conceals viral DNA from cGAS.
• Disruption of the viral core, chemically or physically, exposes HIV-1 DNA, activating innate immune signaling.
• These findings highlight the capsid's role in HIV-1 immune evasion and the potential of capsid-targeting therapies.