The base excision repair pathway is required for efficient lentivirus integration.

Area of Science:

• Molecular Biology
• Virology
• DNA Repair

Background:

• Oxidative DNA damage is a constant threat to genomic integrity.
• The base excision repair (BER) pathway is a primary mechanism for repairing oxidative DNA damage.
• The role of BER proteins in viral infection, particularly lentiviruses, is not well understood.

Purpose of the Study:

• To investigate the involvement of the base excision repair (BER) pathway in human immunodeficiency virus (HIV) infection.
• To determine if other lentiviruses utilize BER proteins for infection.
• To elucidate the specific stage of the HIV life cycle affected by BER deficiency.

Main Methods:

• Conducted an siRNA screen to identify host proteins involved in HIV infection.
• Utilized gene-deleted murine cell lines (Ogg1, Myh, Neil1, Polß) to assess the impact of BER deficiency on viral infection.
• Infected cells with HIV, FIV, and MMLV, and measured viral integration efficiency.
• Performed in vitro integration assays using pre-integration complexes from BER-deficient cells.

Main Results:

• An siRNA screen identified key BER proteins (OGG1, MYH, POLß) essential for efficient HIV infection.
• Murine cells lacking BER genes showed impaired HIV and FIV infection, but not MMLV infection.
• HIV integration into the host chromosome was significantly reduced in BER-deficient cells.
• In vitro assays confirmed reduced integration activity in BER-deficient pre-integration complexes, which was restored by POLß.

Conclusions:

• The entire base excision repair (BER) pathway is implicated in facilitating efficient lentiviral infection.
• BER proteins, particularly POLß, are critical for the integration step of HIV and FIV.
• Lentiviral, but not gammaretroviral, infection efficiency depends on the host cell's BER machinery.