SAMHD1 is an intracellular enzyme that specifically degrades deoxynucleoside triphosphates into
component nucleoside and inorganic triphosphate. In myeloid-derived dendritic cells and macrophages
as well as resting T-cells, SAMHD1 blocks HIV-1 infection through this dNTP triphosphohydrolase
activity by reducing the cellular dNTP pool to a level that cannot support productive reverse
transcription. We now show that, in addition to this direct effect on virus replication, manipulating
cellular SAMHD1 activity can significantly enhance or decrease the anti-HIV-1 efficacy of nucleotide
analogue reverse transcription inhibitors presumably as a result of modulating dNTP pools that
compete for recruitment by viral polymerases. Further, a variety of other nucleotide-based analogues,
not normally considered antiretrovirals, such as the anti-herpes drugs Aciclovir and Ganciclovir and the
anti-cancer drug Clofarabine are now revealed as potent anti-HIV-1 agents, under conditions of low
dNTPs. This in turn suggests novel uses for nucleotide analogues to inhibit HIV-1 in differentiated cells
low in dNTPs.