IP6-stabilised HIV capsids evade cGAS/STING-mediated host immune sensing

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• Human Immunodeficiency Virus type 1 (HIV-1) requires inositol hexakisphosphate (IP6) for capsid stability.
• The role of IP6 in HIV-1 capsid protection and host immune evasion is not fully understood.

Purpose of the Study:

• To investigate the role of IP6 in HIV-1 capsid integrity and innate immune sensing.
• To elucidate the mechanisms by which IP6-deficient HIV-1 triggers antiviral responses.

Main Methods:

• Utilized HIV-1 capsid mutants and CRISPR-Cas9 technology to generate knockout cell lines for specific immune sensors.
• Infected primary macrophages and T-cell lines with wild-type and IP6-deficient HIV-1 strains.
• Assessed capsid integrity, immune activation (cytokine/chemokine production), and viral DNA synthesis.

Main Results:

• HIV-1 lacking IP6 forms unstable capsids, leading to detection by innate immunity and activation of an antiviral state.
• Disruption of IP6 enrichment triggers cytokine and chemokine responses, inhibiting infection.
• Restoring IP6 packaging rescues HIV-1 infectivity and immune evasion.
• Immune sensing of IP6-deficient HIV-1 is dependent on the cGAS-STING pathway and viral DNA synthesis, not capsid detection.

Conclusions:

• IP6 is essential for constructing robust HIV-1 capsids that evade host innate immune surveillance.
• The cGAS-STING pathway, activated by viral DNA synthesis, mediates the immune response to IP6-deficient HIV-1.
• Targeting IP6 packaging could be a strategy to enhance HIV-1 innate immune recognition and control.