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

Area of Science:

• Immunology
• Virology
• Molecular Biology

Background:

• The CARD8 inflammasome is activated by sensing HIV-1 protease activity.
• CARD8 possesses an N-terminal motif mimicking HIV protease substrates, enabling innate immune recognition.
• HIV-1 protease cleavage of this motif triggers CARD8 inflammasome activation.

Purpose of the Study:

• To investigate CARD8 inflammasome activation during HIV-1 cell-to-cell transmission.
• To determine the role of viral protease activity and NLRP3 inflammasome in this process.
• To evaluate how HIV protease variations impact CARD8 sensing.

Main Methods:

• Studied CARD8 inflammasome activation in primary human monocyte-derived macrophages during HIV-1 cell-to-cell transmission.
• Assessed the dependence on viral protease activity and the NLRP3 inflammasome.
• Utilized HIV-1 protease inhibitor-resistant clones to analyze variations in HIV protease function.

Main Results:

• HIV-1 cell-to-cell transmission induces CARD8 inflammasome activation.
• This activation is dependent on viral protease activity and largely independent of NLRP3.
• Mutant HIV-1 proteases differentially cleave and activate CARD8 compared to wildtype.

Conclusions:

• CARD8 activation is a key innate immune response during HIV-1 cell-to-cell spread.
• HIV protease activity is essential for CARD8 sensing in this context.
• Natural variations in HIV protease can modulate innate immune sensing and inflammation.