HIV-1 evades innate immune recognition through specific cofactor recruitment

Area of Science:

• Virology
• Immunology
• Cell Biology

Background:

• Human immunodeficiency virus (HIV)-1 replicates in macrophages without activating innate immunity.
• HIV-1 reverse transcription into double-stranded DNA typically triggers pattern recognition receptors.

Purpose of the Study:

• To investigate if HIV-1 uncoating and nuclear entry are crucial for evading innate immune sensors.
• To determine if manipulating HIV-1 capsid interactions can trigger pattern recognition receptors and type 1 interferon (IFN) secretion.

Main Methods:

• Generated HIV-1 capsid mutants (N74D, P90A) impaired in cofactor interactions (CPSF6, cyclophilins).
• Assessed viral replication, innate sensor activation (NF-κB, IRF3), and IFN production in primary human macrophages.
• Utilized short hairpin RNA to deplete CPSF6 and IFN-receptor blockade to assess IFN's role.
• Investigated the dependency of IFN production on viral reverse transcription and integration.
• Administered a non-immunosuppressive cyclosporine analogue to induce IFN secretion in wild-type HIV-1 infection.

Main Results:

• HIV-1 capsid mutants N74D and P90A failed to replicate due to triggered innate sensors, leading to NF-κB and IRF3 nuclear translocation, type 1 IFN production, and an antiviral state.
• CPSF6 depletion in wild-type HIV-1 infected cells also triggered innate sensors and IFN production.
• IFN-receptor blockade rescued viral replication suppressed by these manipulations, confirming IFN's restrictive role.
• IFN production depended on viral reverse transcription but not integration, suggesting a reverse transcription product as the pathogen-associated molecular pattern.
• Pharmacological induction with a cyclosporine analogue stimulated IFN secretion and an antiviral state in wild-type HIV-1 infection.

Conclusions:

• HIV-1 utilizes CPSF6 and cyclophilins to conceal its replication, thereby evading innate immune sensors in macrophages.
• Disruption of these interactions activates a cell-autonomous innate immune response.
• Viral reverse transcription products act as pathogen-associated molecular patterns triggering IFN secretion.
• Targeting these evasion mechanisms offers a potential strategy for controlling HIV-1 infection.