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

PLoS Pathogens

Chuanping Wang¹  Jacek Skowronski¹  Jinwoo Ahn²  Jennifer Mehrens²  Oliver I. Fregoso³  Michael Emerman³ 

[1] Department of Molecular Biology and Microbiology, Case Western Reserve School of Medicine, Cleveland, Ohio, United States of America;Department of Structural Biology and Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America;Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America

关键词: Viral evolution;    HIV-2;    Primates;    293T cells;    Evolutionary immunology;    Amino acid analysis;    Molecular evolution;    Phylogenetic analysis;   

DOI  :  10.1371/journal.ppat.1003496

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY