Cyclophilin A renders human immunodeficiency virus type 1 sensitive to Old World monkey but not human TRIM5 alpha...

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• TRIM5alpha is a key factor in innate immunity, controlling species-specific replication of retroviruses like HIV-1.
• The peptidyl prolyl isomerase enzyme cyclophilin A's role in TRIM5alpha antiviral activity was previously unclear.

Purpose of the Study:

• To investigate the role of cyclophilin A in TRIM5alpha-mediated antiviral activity against HIV-1.
• To determine how cyclophilin A influences HIV-1 sensitivity to TRIM5alpha restriction in different species.

Main Methods:

• Recruitment of cyclophilin A into HIV-1 virions and capsids.
• Assessing HIV-1 infectivity upon inhibition of cyclophilin A activity (cyclosporine A) or expression (siRNA).
• Utilizing an HIV-1 cyclophilin A binding mutant (CA G89V) to differentiate roles in TRIM5alpha and TRIM-Cyp restriction.
• Expression of simian TRIM5alpha in feline cells to test restriction capabilities.

Main Results:

• Cyclophilin A is recruited to HIV-1 capsids and isomerizes a proline residue, rendering HIV-1 sensitive to TRIM5alpha in Old World monkey cells.
• Inhibition of cyclophilin A restores infectivity of TRIM5alpha-restricted HIV-1, demonstrating cyclophilin A's crucial role.
• TRIM-Cyp utilizes cyclophilin A for capsid recruitment, unlike TRIM5alpha, leading to differential restriction of HIV-1 mutants.
• In human cells, cyclosporine A's effects on HIV-1 are TRIM5alpha-independent, suggesting adaptation to bypass TRIM5alpha.

Conclusions:

• Cyclophilin A isomerization of an HIV-1 capsid proline residue sensitizes it to TRIM5alpha restriction in Old World monkeys.
• Cyclophilin A plays a dual role: mediating TRIM5alpha restriction and potentially interacting with other innate pathways in human cells.
• Understanding these interactions is vital for developing broadly effective antiretroviral therapies.