Antagonism of SAMHD1 is actively maintained in natural infections of simian immunodeficiency virus

Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA 98195.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 12/2013; 110(52). DOI: 10.1073/pnas.1316839110
Source: PubMed


Restriction factors are effectors of the innate immune response to viral pathogens that inhibit viral replication by operating as molecular barriers to steps of the viral life cycle. The restriction factor SAMHD1 blocks lentiviral reverse transcription in myeloid cells and resting CD4+ T cells. Many lineages of lentiviruses, including HIV-2 and other simian immunodeficiency viruses, encode accessory genes that serve to counteract host SAMHD1 restriction by causing degradation of the antiviral factor. The viral accessory protein Vpr is responsible for SAMHD1 degradation in some lineages of lentiviruses, whereas in others the related protein Vpx assumes this task. However, HIV-1 has no SAMHD1 degradation capability, leading to questions about the selective advantage of this activity. We use an evolutionary approach to examine the importance of SAMHD1 antagonism for viral fitness by studying adaptation to host SAMHD1 in natural simian immunodeficiency virus infections of African Green Monkeys. We identified multiple SAMHD1 haplotypes in African Green Monkeys and find that the vpr gene from different strains of Simian Immunodeficiency Virus has adapted to the polymorphisms of the African Green Monkey population in which it is found. Such evidence of viral adaptation to host restriction indicates that SAMHD1 antagonism is actively maintained in natural infections and that this function must be advantageous to viral fitness, despite its absence in HIV-1.

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    • "Vpx from HIV-2, SIV smm (sooty mangabey ) and SIV mac (macaque) all target the SAMHD1 C terminus, whereas SIV mnd-2 (mandrill) and SIV rcm (red-capped mangabey) Vpx induce SAMHD1 degradation dependent on the N-terminal 110 residues. The SAMHD1-degrading Vpr proteins from SIV syk , SIV deb , and SIV agm have varying specificities for the SAMHD1 N or C terminus or even target both (Fregoso et al., 2013; Spragg and Emerman, 2013). Here, we report the crystal structure of the ternary complex of SIV mnd-2 Vpx bound to the N-terminal region and SAM domain of mandrill SAMHD1 (SAMHD1 mnd -NtD) and the WD40 domain of the cullin-4 substrate receptor DCAF1 (DCAF1-CtD). "
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    ABSTRACT: The SAMHD1 triphosphohydrolase inhibits HIV-1 infection of myeloid and resting T cells by depleting dNTPs. To overcome SAMHD1, HIV-2 and some SIVs encode either of two lineages of the accessory protein Vpx that bind the SAMHD1 N or C terminus and redirect the host cullin-4 ubiquitin ligase to target SAMHD1 for proteasomal degradation. We present the ternary complex of Vpx from SIV that infects mandrills (SIVmnd-2) with the cullin-4 substrate receptor, DCAF1, and N-terminal and SAM domains from mandrill SAMHD1. The structure reveals details of Vpx lineage-specific targeting of SAMHD1 N-terminal "degron" sequences. Comparison with Vpx from SIV that infects sooty mangabeys (SIVsmm) complexed with SAMHD1-DCAF1 identifies molecular determinants directing Vpx lineages to N- or C-terminal SAMHD1 sequences. Inspection of the Vpx-DCAF1 interface also reveals conservation of Vpx with the evolutionally related HIV-1/SIV accessory protein Vpr. These data suggest a unified model for how Vpx and Vpr exploit DCAF1 to promote viral replication. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell host & microbe 04/2015; 17(4):489-99. DOI:10.1016/j.chom.2015.03.004 · 12.33 Impact Factor
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    • "Efficient infection of human primary macrophages, dendritic cells and resting CD4 þ T-cells by simian immunodeficiency virus (SIV mac ) requires the accessory protein Vpx (Arfi et al., 2008; Baldauf et al., 2012; Descours et al., 2012; Goujon et al., 2008, 2003, 2007; Spragg and Emerman, 2013). Vpx is essential for both SIV infection of primary macrophages and viral pathogenesis in vivo (Belshan et al., 2006; Fletcher et al., 1996; Gibbs et al., 1995; Hirsch et al., 1998). "
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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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    • "This evolutionary arms-race likely led to species specificity (Fregoso et al., 2013; Wei et al., 2014) and emphasizes the importance of the conservation of Vpx (Vpr) mediated SAMHD1 antagonism for lentiviruses. In agreement with this notion, SAMHD1 antagonism is actively maintained in natural infections, as exemplified by SIVagm vpr adaptations to SAMHD1 polymorphisms found in the African green monkey population (Spragg and Emerman, 2013). "
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    ABSTRACT: Vpx is a protein encoded by members of the HIV-2/SIVsmm and SIVrcm/SIVmnd-2 lineages of primate lentiviruses, and is packaged into viral particles. Vpx plays a critical role during the early steps of the viral life cycle and has been shown to counteract SAMHD1, a restriction factor in myeloid and resting T cells. However, it is becoming evident that Vpx is a multifunctional protein in that SAMHD1 antagonism is likely not its sole role. This review summarizes the current knowledge on this X-traordinary protein.
    Frontiers in Microbiology 04/2014; 5:126. DOI:10.3389/fmicb.2014.00126 · 3.99 Impact Factor
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