HIV-1 exploits the Fanconi anemia pathway for viral DNA integration

• Published in: Cell reports (Cambridge) 2022-05, Vol.39 (8), p.110840-110840, Article 110840
• Main Authors: Fu, Shaozu, Phan, An Thanh, Mao, Dexin, Wang, Xinlu, Gao, Guangxia, Goff, Stephen P., Zhu, Yiping
• Format: Article
• Language: English
• Subjects: DNA Damage; DNA Repair; DNA, Viral - genetics; DNA, Viral - metabolism; Fanconi Anemia - genetics; Fanconi Anemia - metabolism; Fanconi Anemia Complementation Group D2 Protein - metabolism; Fanconi Anemia Complementation Group Proteins - genetics; Fanconi Anemia Complementation Group Proteins - metabolism; Fanconi anemia DNA repair pathway; HIV-1; HIV-1 - genetics; HIV-1 - metabolism; Humans; integration; Ubiquitination
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110840

The integration of HIV-1 DNA into the host genome results in single-strand gaps and 2-nt overhangs at the ends of viral DNA, which must be repaired by cellular enzymes. The cellular factors responsible for the DNA damage repair in HIV-1 DNA integration have not yet been well defined. We report here that HIV-1 infection potently activates the Fanconi anemia (FA) DNA repair pathway, and the FA effector proteins FANCI-D2 bind to the C-terminal domain of HIV-1 integrase. Knockout of FANCI blocks productive viral DNA integration and inhibits the replication of HIV-1. Finally, we show that the knockout of DNA polymerases or flap nuclease downstream of FANCI-D2 reduces the levels of integrated HIV-1 DNA, suggesting these enzymes may be responsible for the repair of DNA damages induced by viral DNA integration. These experiments reveal that HIV-1 exploits the FA pathway for the stable integration of viral DNA into host genome. [Display omitted] •HIV-1 infection activates the Fanconi anemia (FA) DNA repair pathway•HIV-1 integrase interacts with FANCI-D2 complex•Depletion of FA proteins and downstream enzymes inhibits HIV-1 DNA integration Fu et al. show that HIV-1 integrase interacts with FANCI-D2 complex, and HIV-1 DNA integration activates the Fanconi anemia (FA) pathway. They discover that the depletion of FA proteins and downstream enzymes blocks viral DNA integration, suggesting that the FA pathway is exploited by HIV-1 to repair DNA damage induced by viral DNA integration.