Duggal, N. K. & Emerman, M. Evolutionary conflicts between viruses and restriction factors shape immunity. Nature Rev. Immunol. 12, 687-695

1] Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, Washington 98109, USA. [2] Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Nature Reviews Immunology (Impact Factor: 34.99). 09/2012; 12(10):687-95. DOI: 10.1038/nri3295
Source: PubMed


Host restriction factors are potent, widely expressed intracellular blocks to viral replication that are an important component of the innate immune response to viral infection. However, viruses have evolved mechanisms that antagonize restriction factors. Through evolutionary pressure for both host survival and virus replication, an evolutionary 'arms race' has developed that drives continuous rounds of selection for beneficial mutations in the genes encoding restriction factors and their viral antagonists. Because viruses can evolve faster than their hosts, the innate immune system of modern-day vertebrates is for the most part optimized to defend against ancient viruses, rather than newer viral threats. Thus, the evolutionary history of restriction factors might, in part, explain why humans are susceptible or resistant to the viruses present in the modern world.

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Available from: Nisha K Duggal, Nov 19, 2015
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    • "Incessant cycles of genetic conflict between mammalian hosts and retroviruses resulted in the emergence of host gene products that can directly inhibit retroviruses including HIV-1 (Duggal and Emerman, 2012). Among these 'retrovirus restriction factors' are the apolipoprotein B mRNA editing enzyme catalytic polypeptide-3 (APOBEC3 or A3) deaminases (Malim, 2009). "
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    ABSTRACT: APOBEC1 is a cytidine deaminase involved in cholesterol metabolism that has been linked to retrovirus restriction, analogous to the evolutionarily-related APOBEC3 proteins. In particular, murine APOBEC1 was shown to inhibit Friend retrovirus (FV) in vitro, generating high levels of C-to-T and G-to-A mutations. These observations raised the possibility that FV infection might be altered in APOBEC1-null mice. To examine this question directly, we infected wild-type and APOBEC1-null mice with FV complex and evaluated acute infection levels. Surprisingly, APOBEC1-null mice exhibited similar cellular infection levels and plasma viremia relative to wild-type mice. Moreover, next-generation sequencing analyses revealed that in contrast to APOBEC3, APOBEC1 did not enhance retroviral C-to-T and G-to-A mutational frequencies in genomic DNA. Thus, APOBEC1 neither inhibited nor significantly drove the molecular evolution of FV in vivo. Our findings reinforce that not all retrovirus restriction factors characterized as potent in vitro may be functionally relevant in vivo.
    Virology 10/2014; 468-470C:601-608. DOI:10.1016/j.virol.2014.09.006 · 3.32 Impact Factor
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    • "Genetic conflict between host and viral genomes can lead to the rapid accumulation of amino acid replacement changes (dN) relative to synonymous changes (dS). This phenomenon of positive selection (dN/dS >1) is one hallmark of the evolutionary 'battle' that occurs between host antiviral factors and their pathogen antagonists (Emerman and Malik 2010; Duggal and Emerman 2012). Although positive selection is not typically observed in other host genes, multiple antiviral factors contain genetic 'signatures' of positive selection (Bustamante et al. 2005; Subramanian and Kumar 2006). "
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    ABSTRACT: Tripartite motif-containing protein 22 (TRIM22) is a novel interferon-induced protein that potently inhibits the replication of evolutionarily diverse viruses, including human immunodeficiency virus type 1 (HIV-1). Altered TRIM22 expression is associated with a variety of diseases such as multiple sclerosis, cancer and autoimmune diseases. The factors that influence TRIM22 expression and antiviral activity are largely unknown. We adopted an evolution-guided functional approach to identify potential genetic determinants of TRIM22 function. Evolutionary analysis of TRIM22 from mammals spanning >100 million years of evolution demonstrated that the evolution of TRIM22 has been shaped by ancient and variable positive selection. We showed that positive selection is operating on multiple residues that cluster in putative functional regions and are predicted to be functionally damaging. Interestingly, the second most prevalent TRIM22 single nucleotide polymorphism (SNP) in humans (rs1063303) is located at one of these positively selected residues. We showed that the frequency of rs1063303:G>C varies up to 10-fold between ethnicities. The SNP rs1063303:G>C variant also had an inverse functional impact where it increased TRIM22 expression and decreased the antiviral activity of TRIM22. Together, our data characterizes the extensive genetic variation in TRIM22 and identifies rs1063303:G>C as a highly prevalent SNP that influences its function. This article is protected by copyright. All rights reserved.
    Human Mutation 09/2014; 35(9). DOI:10.1002/humu.22595 · 5.14 Impact Factor
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    • "In addition, the PLVs in the HIV-1 lineage encode an additional accessory gene, vpu, whereas those in the HIV-2 lineage encode the other unique gene, vpx2. Interestingly, recent studies focusing on the interplay between viral and host proteins345 have provided lines of evidence for supporting “Red Queen hypothesis”6 or “evolutionary arms race”, which is an important assumption proposed for the co-evolution of PLVs and their host species. For instance, the accessory proteins such as Vif, Vpx, Vpu, and Nef encoded by PLVs have been acquired and evolved their abilities to antagonize cellular anti-PLV restriction factors such as apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G (APOBEC3G)7, SAM domain and HD domain 1 (SAMHD1)89, and bone marrow stromal antigen 2 ([BST2], also known as tetherin, CD317, and HM1.24; hereinafter referred to as “tetherin”)1011. "
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    ABSTRACT: Primate lentiviruses including human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency viruses (SIVs) evolved through the acquisition of antagonists against intrinsic host restriction factors, such as tetherin. It is widely accepted that HIV-1 has emerged by zoonotic transmission of SIV in chimpanzee (SIVcpz), and that SIVcpz Nef protein antagonizes chimpanzee tetherin. Although Nef of SIVcpz shares a common ancestor with that of SIVrcm, an SIV in red-capped mangabey (Cercocebus torquatus), it remains unclear whether SIVrcm Nef can antagonize tetherin of its natural host. In this study, we determine the sequence of red-capped mangabey tetherin for the first time and directly demonstrate that SIVrcm Nef is the bona fide antagonist of red-capped mangabey tetherin. These findings suggest that SIVrcm Nef is the functional ancestor of SIVcpz Nef. Moreover, molecular phylogenetic analyses reveal that tetherins of the genus Cercocebus have experienced adaptive evolution, which is presumably promoted by primate lentiviruses.
    Scientific Reports 07/2014; 4:5529. DOI:10.1038/srep05529 · 5.58 Impact Factor
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