Evolutionary and Functional Analyses of the Interaction between the Myeloid Restriction Factor SAMHD1 and the Lentiviral Vpx Protein

Institut de Génétique Humaine, Centre National de la Recherche Scientifique, Unité Propre de Recherche 1142, Laboratoires de Virologie Moléculaire, 34000 Montpellier, France.
Cell host & microbe (Impact Factor: 12.33). 02/2012; 11(2):205-17. DOI: 10.1016/j.chom.2012.01.007
Source: PubMed


SAMHD1 has recently been identified as an HIV-1 restriction factor operating in myeloid cells. As a countermeasure, the Vpx accessory protein from HIV-2 and certain lineages of SIV have evolved to antagonize SAMHD1 by inducing its ubiquitin-proteasome-dependent degradation. Here, we show that SAMHD1 experienced strong positive selection episodes during primate evolution that occurred in the Catarrhini ancestral branch prior to the separation between hominoids (gibbons and great apes) and Old World monkeys. The identification of SAMHD1 residues under positive selection led to mapping the Vpx-interaction domain of SAMHD1 to its C-terminal region. Importantly, we found that while SAMHD1 restriction activity toward HIV-1 is evolutionarily maintained, antagonism of SAMHD1 by Vpx is species-specific. The distinct evolutionary signature of SAMHD1 sheds light on the development of its antiviral specificity.

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    • "SAMHD1 is a newly discovered HIV-1 host restriction factor, which can be degraded by the viral accessory protein Vpx of HIV-2 and some simian immunodeficiency viruses (SIVs) [19]. However, HIV-1 lost the Vpx protein during the evolutionary process [20]. Therefore, SAMHD1 currently differs from other HIV-1 host restriction factors by being one of the host restriction factors that cannot be antagonized by HIV-1 [8]. "
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    ABSTRACT: SAM domain and HD domain 1 (SAMHD1) is a newly discovered human immunodeficiency virus (HIV)-1 host restriction factor with high expression in HIV-1-non-permissive cells and low expression in HIV-1-permissive cells. The regulatory mechanism of SAMHD1 expression is still unclear. We examined the relationship between the expression levels of SAMHD1 mRNA and protein and microRNA-181 (miR-181) level in different cell lines. MiR-181 level was negatively correlated with SAMHD1 expression level. By examining the impact of miR-181 on SAMHD1 3' untranslated region (UTR) reporter luciferase activity and on SAMHD1 mRNA and argonaute RISC catalytic component 2 (AGO2) binding, we found that miR-181 acted directly on the SAMHD1 3' UTR and regulated SAMHD1 mRNA levels after transcription. MiR-181 over-expression significantly reduced the level of SAMHD1 expression in THP-1 cells; miR-181 inhibition up-regulated SAMHD1 expression in THP-1 and Jurkat cells. Our results suggest that miR-181 regulates the level of post-transcriptional SAMHD1 expression negatively by directly binding to the 3' UTR in SAMHD1.
    Biochemical and Biophysical Research Communications 09/2014; 452(3). DOI:10.1016/j.bbrc.2014.08.151 · 2.30 Impact Factor
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    • "This work explores the different features of human SAMHD1 polymorphisms . We have focused our experiments on studying human polymorphisms on residues that have been positively selected during primate speciation ( Laguette et al . , 2012 ; Lim et al . , 2012 ) . We initially tested for the ability of these polymorph - isms to block HIV - 1 and HIV - 2 infection . None of the tested SAMHD1 polymorphisms lost the ability to block HIV - 1 or HIV - 2 infection . To further understand the anti - viral activity of these variants , we tested for their ability to block EIAV , a"
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    ABSTRACT: SAMHD1 is a human restriction factor that prevents efficient infection of macrophages, dendritic cells and resting CD4+ T cells by HIV-1. Here we explored the antiviral activity and biochemical properties of human SAMHD1 polymorphisms. Our studies focused on human SAMHD1 polymorphisms that were previously identified as evolving under positive selection for rapid amino acid replacement during primate speciation. The different human SAMHD1 polymorphisms were tested for their ability to block HIV-1, HIV-2 and equine infectious anemia virus (EIAV). All studied SAMHD1 variants block HIV-1, HIV-2 and EIAV infection when compared to wild type. We found that these variants did not lose their ability to oligomerize or to bind RNA. Furthermore, all tested variants were susceptible to degradation by Vpx, and localized to the nuclear compartment. We tested the ability of human SAMHD1 polymorphisms to decrease the dNTP cellular levels. In agreement, none of the different SAMHD1 variants lost their ability to reduce cellular levels of dNTPs. Finally, we found that none of the tested human SAMHD1 polymorphisms affected the ability of the protein to block LINE-1 retrotransposition.
    Virology 07/2014; 460(461):34-44. DOI:10.1016/j.virol.2014.04.023 · 3.35 Impact Factor
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    • "Our database has been used for developing new markers in multigene phylogenetic studies (Zhou et al. 2011; Hassanin et al. 2013), and also as a source of large-scale molecular data in phylogenomic (Parker et al. 2013; Romiguier et al. 2013), molecular dating (Schrago and Voloch 2013), and evolutionary genomic (Galtier et al. 2009; Romiguier et al. 2010; Rorick and Wagner 2011; Lartillot 2013) analyses. The highquality codon alignments have also been utilized as benchmark empirical datasets for testing new analytical methods (Egan et al. 2008; López-Giráldez and Townsend 2011; Li and Drummond 2012; Wu et al. 2013) and for detecting footprints of purifying or positive selection (Jobson et al. 2010; Laguette et al. 2012). Finally, the inferred ML gene trees have served for assessing the performance of supertree methods (Scornavacca et al. 2008; Ranwez et al. 2010). "
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    ABSTRACT: Comparative genomic studies extensively rely on alignments of orthologous sequences. Yet, selecting, gathering and aligning orthologous exons and protein-coding sequences (CDS) that are relevant for a given evolutionary analysis can be a difficult and time-consuming task. In this context, we developed OrthoMaM, a database of ORTHOlogous MAmmalian Markers describing the evolutionary dynamics of orthologous genes in mammalian genomes using a phylogenetic framework. Since its first release in 2007, OrthoMaM has regularly evolved, not only to include newly available genomes, but also to incorporate up-to-date software in its analytic pipeline. This eighth release integrates the 40 complete mammalian genomes available in Ensembl v73, and provides alignments, phylogenies, evolutionary descriptor information and functional annotations for 13,404 single-copy orthologous CDS and 6,953 long exons.The graphical interface allows to easily explore OrthoMaM to identify markers with specific characteristics (e.g., taxa availability, alignment size, %G+C, evolutionary rate, chromosome location). It hence provides an efficient solution to sample pre-processed markers adapted to user specific needs. Since its first release, OrthoMaM has proven to be a valuable resource for researchers interested in mammalian phylogenomics, evolutionary genomics, and has served as a source of benchmark empirical datasets in several methodological studies. OrthoMaM is available for browsing, query and complete or filtered downloads at
    Molecular Biology and Evolution 04/2014; DOI:10.1093/molbev/msu132 · 9.11 Impact Factor
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