CARD8 inflammasome activation during HIV-1 cell-to-cell transmission

Area of Science:

• Immunology
• Virology
• Molecular Biology

Background:

• CARD8 (Caspase-recruitment domain family member 8) recognizes HIV-1 protease activity.
• HIV-1 protease cleaves CARD8's N-terminal mimic motif, triggering inflammasome activation.
• Understanding CARD8's role in HIV-1 cell-to-cell transmission is crucial for innate immunity research.

Purpose of the Study:

• To investigate CARD8 inflammasome activation during HIV-1 cell-to-cell transmission via a viral synapse.
• To determine the role of HIV protease activity and variation in CARD8 sensing.
• To assess the contribution of NLRP3 inflammasome in this context.

Main Methods:

• Studied CARD8 inflammasome activation in primary human monocyte-derived macrophages during HIV-1 cell-to-cell transfer.
• Utilized HIV-1 protease inhibitor resistant clones to analyze viral determinants of CARD8 sensing.
• Assessed CARD8 activation in response to wildtype and mutant HIV-1 proteases.

Main Results:

• HIV-1 cell-to-cell transmission robustly induces CARD8 inflammasome activation.
• This activation is dependent on HIV protease activity but largely independent of NLRP3 inflammasome.
• Mutant HIV-1 proteases exhibit differential cleavage and activation of CARD8 compared to wildtype.

Conclusions:

• CARD8 senses HIV-1 protease activity during cell-to-cell transmission.
• HIV-1 protease variation influences both viral polyprotein processing and innate immune sensing.
• These findings highlight the impact of viral protease evolution on host inflammatory responses.