Evolutionary Toggling of Vpx/Vpr Specificity Results in Divergent Recognition of the Restriction Factor SAMHD1

Samhd1 is a host restriction factor that blocks the ability of lentiviruses such as hiv-1 to undergo reverse transcription in myeloid cells and resting t-cells. this restriction is alleviated by expression of the lentiviral accessory proteins vpx and vpr (vpx/vpr),which target samhd1 for proteasome-mediated degradation. however,the precise determinants within samhd1 for recognition by vpx/vpr remain unclear. here we show that evolution of vpx/vpr in primate lentiviruses has caused the interface between samhd1 and vpx/vpr to alter during primate lentiviral evolution. using multiple hiv-2 and siv vpx proteins,we show that vpx from the hiv-2 and sivmac lineage,but not vpx from the sivmnd2 and sivrcm lineage,require the c-terminus of samhd1 for interaction,ubiquitylation,and degradation. on the other hand,the n-terminus of samhd1 governs interactions with vpx from sivmnd2 and sivrcm,but has little effect on vpx from hiv-2 and sivmac. furthermore,we show here that this difference in samhd1 recognition is evolutionarily dynamic,with the importance of the n- and c-terminus for interaction of samhd1 with vpx and vpr toggling during lentiviral evolution. we present a model to explain how the head-to-tail conformation of samhd1 proteins favors toggling of the interaction sites by vpx/vpr during this virus-host arms race. such drastic functional divergence within a lentiviral protein highlights a novel plasticity in the evolutionary dynamics of viral antagonists for restriction factors during lentiviral adaptation to its hosts. © 2013 fregoso et al.