Abstract
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.
Highlights
HIV-1, HIV-2, and other primate lentiviruses encode accessory virulence factors that serve to enhance viral infectivity
Chimeras and truncations were based on previous results which showed that SAMHD1 is still catalytically active and able to form tetramers when truncated at the C-terminus or the N-terminus [29]
We found that when WT, dendritic cells (DCs), or DN rhesus SAMHD1 was incubated with a preformed Cul4-DCAF1cVpxSIVmac E3 ubiquitin ligase complex, WT and DN SAMHD1 were readily ubiquitylated in the presence of Vpx, DC SAMHD1 was not (Figure 4C, left panel)
Summary
HIV-1, HIV-2, and other primate lentiviruses encode accessory virulence factors that serve to enhance viral infectivity. This is largely achieved through increasing virus replication by counteracting host antiviral proteins, known as restriction factors [1]. One such restriction factor, SAMHD1, is a deoxynucleoside triphosphate triphosphohydrolase that suppresses cellular dNTP pools [2,3]. SAMHD1, is a deoxynucleoside triphosphate triphosphohydrolase that suppresses cellular dNTP pools [2,3] This prevents efficient infection of monocytes, dendritic cells (DCs), and mature macrophages by reducing the dNTP pools below the levels needed for reverse transcription of viral RNA [4,5]. SAMHD1 is composed of two structural domains: a sterile alpha motif (SAM) domain, responsible for protein-protein interactions, and a histidine-aspartic (HD) domain, responsible for the phosphohydrolase activity of the protein
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