TY - JOUR
T1 - The ability of primate lentiviruses to degrade the monocyte restriction factor SAMHD1 preceded the birth of the viral accessory protein Vpx
AU - Lim, Efrem S.
AU - Fregoso, Oliver I.
AU - McCoy, Connor O.
AU - Matsen, Frederick A.
AU - Malik, Harmit S.
AU - Emerman, Michael
N1 - Funding Information:
The following reagents were obtained through the National Institutes of Health (NIH) AIDS Research and Reference Reagent Program, Division of AIDS, National Institute of Allergy and Infectious Diseases (NIAID), NIH: pSIVmac239Δnef Deletion Mutant (2477) from Ronald Desrosiers; SIVcpzTAN2.69 (11497) and SIVcpzTAN3.1 (11498) from Jun Takehisa, Matthias Kraus, and Beatrice Hahn; HIV-2 7312a and SIVagmGrivet from Beatrice Hahn; and HIV-1 Q23-17 from Julie Overbaugh. We are grateful to the FHCRC Genomics Shared Resources for assistance, and to Alex Compton, Matthew Daugherty, and Nisha Duggal for comments on the manuscript. This work was supported by NIH grant R01 AI30937 (to M.E.) and a National Science Foundation (NSF) Career grant (to H.S.M.). H.S.M. is an Early-Career Scientist of the Howard Hughes Medical Institute. E.S.L. is supported by the University of Washington Helen Riaboff Whiteley Graduate Fellowship.
PY - 2012/2/16
Y1 - 2012/2/16
N2 - The human SAMHD1 protein potently restricts lentiviral infection in dendritic cells and monocyte/macrophages but is antagonized by the primate lentiviral protein Vpx, which targets SAMHD1 for degradation. However, only two of eight primate lentivirus lineages encode Vpx, whereas its paralog, Vpr, is conserved across all extant primate lentiviruses. We find that not only multiple Vpx but also some Vpr proteins are able to degrade SAMHD1, and such antagonism led to dramatic positive selection of SAMHD1 in the primate subfamily Cercopithecinae. Residues that have evolved under positive selection precisely determine sensitivity to Vpx/Vpr degradation and alter binding specificity. By overlaying these functional analyses on a phylogenetic framework of Vpr and Vpx evolution, we can decipher the chronology of acquisition of SAMHD1-degrading abilities in lentiviruses. We conclude that vpr neofunctionalized to degrade SAMHD1 even prior to the birth of a separate vpx gene, thereby initiating an evolutionary arms race with SAMHD1.
AB - The human SAMHD1 protein potently restricts lentiviral infection in dendritic cells and monocyte/macrophages but is antagonized by the primate lentiviral protein Vpx, which targets SAMHD1 for degradation. However, only two of eight primate lentivirus lineages encode Vpx, whereas its paralog, Vpr, is conserved across all extant primate lentiviruses. We find that not only multiple Vpx but also some Vpr proteins are able to degrade SAMHD1, and such antagonism led to dramatic positive selection of SAMHD1 in the primate subfamily Cercopithecinae. Residues that have evolved under positive selection precisely determine sensitivity to Vpx/Vpr degradation and alter binding specificity. By overlaying these functional analyses on a phylogenetic framework of Vpr and Vpx evolution, we can decipher the chronology of acquisition of SAMHD1-degrading abilities in lentiviruses. We conclude that vpr neofunctionalized to degrade SAMHD1 even prior to the birth of a separate vpx gene, thereby initiating an evolutionary arms race with SAMHD1.
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U2 - 10.1016/j.chom.2012.01.004
DO - 10.1016/j.chom.2012.01.004
M3 - Article
C2 - 22284954
AN - SCOPUS:84857347109
SN - 1931-3128
VL - 11
SP - 194
EP - 204
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 2
ER -