Cyclophilin A Facilitates HIV-1 DNA Integration

Area of Science:

• Virology
• Molecular Biology
• Immunology

Background:

• Cyclophilin A (CypA) is a host protein known to bind the HIV-1 capsid.
• CypA facilitates HIV-1 reverse transcription and nuclear entry.
• The precise role of CypA in later stages of HIV-1 infection, such as integration, remains unclear.

Purpose of the Study:

• To investigate the role of Cyclophilin A (CypA) in HIV-1 integration.
• To determine if CypA-capsid interaction influences post-nuclear entry steps of HIV-1 infection.
• To elucidate the mechanism by which CypA might affect HIV-1 integration.

Main Methods:

• Challenging CypA-expressing and CypA-depleted cells with HIV-1.
• Using cyclosporin A to inhibit CypA-capsid binding.
• Analyzing HIV-1 capsid mutants with impaired CypA binding.
• Assessing the in vitro integration activity of HIV-1 preintegration complexes (PICs).

Main Results:

• CypA depletion significantly reduced HIV-1 integration, independent of reverse transcription, nuclear entry, or TRIM5α presence.
• Inhibition of CypA-capsid binding and use of CypA-binding deficient capsid mutants blocked integration.
• PICs from CypA-depleted cells showed reduced in vitro integration activity.
• Addition of CypA protein stimulated PIC integration activity.

Conclusions:

• Cyclophilin A (CypA) plays a novel and essential role in promoting HIV-1 integration.
• CypA enhances HIV-1 integration by directly stimulating the activity of the preintegration complex.
• These findings reveal a new mechanism of HIV-1 replication involving host-pathogen interactions.