Unlike closely related protein family members Cul1, Cul4 and Cul5, which are hijacked by HIV-1 to support viral infection [22], our data demonstrate that Cul3 acts as a negative regulator of HIV-1 infection and further elucidate the mode of action by which Cul3 exerts this restrictive effect on HIV-1. This evidence concerns the gene CUL3 and HIV-1 infection.