CTNNBL1 restricts HIV-1 replication by suppressing viral DNA integration into the cell genome

Retroviral integration is mediated by a unique enzymatic process shared by all retroviruses and retrotransposons. During integration, double-stranded linear viral DNA is inserted into the host genome in a process catalyzed by viral-encoded integrase (IN). However, host cell defenses against HIV-1 integration are not clear. This study identifies β-catenin-like protein 1 (CTNNBL1) as a potent inhibitor of HIV-1 integration via association with viral-encoded integrase (IN) and its cofactor, lens epithelium-derived growth factor/p75. CTNNBL1 overexpression blocks HIV-1 integration and inhibits viral replication, whereas CTNNBL1 depletion significantly upregulates HIV-1 integration into the genome of various target cells. Further, CTNNBL1 expression is downregulated in CD4⁺ T cells by activation, and CTNNBL1 depletion also facilitates HIV-1 integration in resting CD4⁺ T cells. Thus, host cells may employ CTNNBL1 to inhibit HIV-1 integration into the genome. This finding suggests a strategy for the treatment of HIV infections.