Background Interferon-a (IFN-a) potently inhibits both the early and late phases of HIV replication by inducing diverse unknown antiviral host factors. The dGTP-regulated deoxynucleoside triphosphate (dNTP) hydrolase SAMHD1 is a restriction factor that inhibits the reverse transcription (RT) of HIV. SAMHD1 depletes dNTP levels in quiescent cells such as myeloid cells or resting CD4+ T lymphocytes. HIV-2 and its SIVsm and SIVmac close relatives encode a protein termed Vpx that counteracts this antiviral mechanism of “nucleotide depletion” by promoting SAMHD1 degradation, thus allowing the RT of retroviruses to proceed. It is also proposed that Vpx targets the IFN-a-induced APOBEC3A (A3A) antiviral protein for degradation. Here, we investigated whether IFN-a cooperates with nucleotide depletion to counteract HIV.