DOCSLIB.ORG

Evolutionary Journey of the Retroviral Restriction Gene Fv1

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Evolutionary Journey of the Retroviral Restriction Gene Fv1 Evolutionary journey of the retroviral restriction gene Fv1 George R. Younga, Melvyn W. Yapa, Johan R. Michauxb,c, Scott J. Steppand, and Jonathan P. Stoyea,e,1 aRetrovirus-Host Interactions Laboratory, The Francis Crick Institute, London NW1 1AT, United Kingdom; bLaboratoire de Génétique de la Conservation, Université de Liège, 4000 Liège, Belgium; cUMR Animal, Santé, Territoires, Risques et Ecosystèmes (ASTRE), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (CIRAD), Campus International de Baillarguet, Université de Montpellier, 34398 Montpellier, France; dDepartment of Biological Science, Florida State University, Tallahassee, FL 32304; and eDepartment of Medicine, Imperial College London, London SW7 2AZ, United Kingdom Edited by Stephen P. Goff, Columbia University Medical Center, New York, NY, and approved August 17, 2018 (received for review May 18, 2018) Both exogenous and endogenous retroviruses have long been this apparently recent ancestry, the pol gene of the progenitor studied in mice, and some of the earliest mouse studies focused on virus is lacking, and neither LTR has been discerned (8). the heritability of genetic factors influencing permissivity and Searches for intact representatives of the progenitor revealed no resistance to infection. The prototypic retroviral restriction factor, closely related ERVs, and Fv1 shares only 43% amino acid identity Fv1, is now understood to exhibit a degree of control across mul- with its nearest neighbor in the mouse genome, MuERV-L (ERV Mus tiple retroviral genera and is highly diverse within . To better with a leucine tRNA primer binding site) (8). This paradox may Fv1 understand the age and evolutionary history of , a comprehen- result from incomplete representation of exogenous viruses among sive survey of the Muroidea was conducted, allowing the progen- those endogenized and fixed but, equally, may suggest a longer itor integration to be dated to ∼45 million years. Intact coding and more complex evolutionary history. Indeed, Southern blot- potential is visible beyond Mus, and sequence analysis reveals strong signatures of positive selection also within field mice, Apo- ting revealed hybridizing digestion fragments within the genus demus. Fv1’s survival for such a period implies a recurring and Mastomys (12), although this was never further studied. shifting retroviral burden imparting the necessary selective pres- Here, we have sought to more accurately determine the origin sures—an influence likely also common to analogous factors. Re- of Fv1 and to use a phylogenetic approach to inform on the MICROBIOLOGY gions of Fv1 adapt cooperatively, highlighting its preference for historical selection pressures that have shaped its restriction repeated structures and suggesting that this functionally con- specificities and preserved the gene through evolutionary time. strained aspect of the retroviral capsid lattice presents a common target in the evolution of intrinsic immunity. Results Resolving the History of the Fv1 Locus. Within Mus, Fv1 (GRCm38 restriction factor | evolution | host–virus interactions | retrovirus Chr4:147,868,979–147,870,358) is located in an ∼5-kb region between Migration and invasion inhibitory protein (Miip) and hile a variety of viruses occasionally integrate as endoge- Mitofusin 2 (Mfn2) (Fig. 1). The shared direction and relative Wnous viral elements (1), the absolute requirement for an separation of this pair are common among assembled genomes integrated proviral stage is the defining feature of retroviral from humans and mice through to chickens (diverging ∼310 Mya), replication. When infection occurs within a germ cell, endoge- nous retroviruses (ERVs) may be inherited in a Mendelian Significance manner and hence, form a partial “fossil record” of historic viral burdens. Although originally unappreciated, retroviruses, as fil- We have charted the evolution of the capsid-binding retroviral terable, transmissible pathogens, have been studied since the late restriction factor Fv1 through murid evolution, extending its 1800s. The earliest breeding of inbred animals both facilitated age to ∼45 million years. Functionality can be found outside of and was necessitated by the study of ERVs and exogenous ret- the genus Mus, and shared signatures of positive selection are “ ” roviruses as the agents of heritable cancer (2). Research de- visible across species. Modeling suggests that maintenance for veloping these themes in mice led to the description of Friend these extended periods can only be parsimoniously explained virus susceptibility 1 (Fv1), a dominant locus conferring pro- by repeated selection events—waves of retroviral infection tection from otherwise lethal challenges with murine leukemia throughout murid evolution. Our results complement and ex- virus (MLV) (3, 4). Within common laboratory lines, two alleles α b n tend findings with TRIM5 and suggest that conserved fea- can be observed, Fv1 and Fv1 , that were identified in BALB/c tures of retroviral capsid lattice assemblies may be common and NIH-Swiss mice, respectively. Each allele confers resistance targets in convergent evolution of intrinsic defenses to retro- to virus of the opposing N and B tropism and may be additively viral infection. Functional constraints on capsid structure may combined (5, 6). prevent effective escape of host factors and result in cyclical The molecular cloning of Fv1 revealed its derivation from a coevolution, which is visible in the evolution of Fv1. retroviral gag gene (7, 8). While many examples of such co-options for host defense have been reported, these are most frequently Author contributions: G.R.Y., J.R.M., S.J.S., and J.P.S. designed research; G.R.Y. and products of env operating through receptor blockade (9). Fv1’s M.W.Y. performed research; J.R.M. and S.J.S. contributed new reagents/analytic tools; presumably more unique mode of restriction, indirectly de- G.R.Y. and M.W.Y. analyzed data; and G.R.Y. and J.P.S. wrote the paper. termined to be through capsid (CA) binding (10), has remained The authors declare no conflict of interest. elusive. Similarly, while its domain organization has been char- This article is a PNAS Direct Submission. acterized, the protein has not proven amenable to crystallization, Published under the PNAS license. and all studies to date have had a necessarily genetic basis. Nev- Data deposition: The sequences reported in this paper have been deposited in the Gen- ertheless, recent work has expanded the scope of restriction be- Bank database (accession nos. MH001948-69 and MH727610-4). yond the gammaretroviruses to lenti- and spumaviruses (11). 1To whom correspondence should be addressed. Email: [email protected]. Based on instances of absence within certain Mus species and This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. on its absence in Rattus, previous estimates have placed in- 1073/pnas.1808516115/-/DCSupplemental. tegration of Fv1’s progenitor virus at 4–7 Mya (12, 13). Despite www.pnas.org/cgi/doi/10.1073/pnas.1808516115 PNAS Latest Articles | 1of6 Fv1 > < Miip < Mfn2 Oryctolagus cuniculus Ictidomys tridecemlineatus Marmota marmota Fukomys damarensis Heterocephalus glaber Octodon degus Chinchilla lanigera Castor canadensis Dipodomys ordii Jaculus jaculus Spalax galili Cricetulus griseus Mesocricetus auratus Myodes glareolus Ellobius talpinus Microtus ochrogaster Peromyscus maniculatus Neotoma lepida Psammomys obesus Meriones unguiculatus Rattus norvegicus Mus musculus Fig. 1. Fv1 is found across the Muroidea. Representation of the multiple alignment of 22 species from the 5′ UTR of Miip to the 3′ UTR of Mfn2. Regions masked by RepeatMasker as deriving from repetitive elements (including Fv1) are show in red, with the remaining sequence and genic regions in black and alignment gaps represented as linking lines. The region encompassing Fv1 is shaded in blue and can be seen in genera from Mus to Spalax, where larger regions of the progenitor virus can also be identified (lighter blue shading). and they thus present a useful framework within which the pres- within the Spalacidae. No sequences identified in this screen ence or absence of Fv1 can be established. contained intact ORFs. To initially investigate the presence of Fv1 immediately be- Twenty-two assemblies contained single contigs bridging Miip and yond the genus Mus, we analyzed three sequences from the ge- Mfn2 and were used to build an alignment of the region (species for nus Apodemus: Apodemus sylvaticus from an archived genome which both genes were not assembled together were excluded, as assembly and Apodemus uralensis and Apodemus semosus unassembled regions would otherwise be indistinguishable from from targeted assemblies of the region. Fv1 was present in all genuinely absent sequence). Comparisons revealed a high degree of instances, with complete ORFs visible in A. sylvaticus and variability due largely to the activity of transposable elements (TEs) A. uralensis. Both ORFs exhibited activity directed against (Fig. 1). This variability, combined with the multiple points of erro- MLVs when assayed for restriction capacity (Table 1). neous homology presented by TEs, posed a significant challenge and The divergence of the Apodemini and Murini tribes predates necessitated the use of a repeat-aware alignment program, FSA (15), that of the Murini and Praomyini (14), represented by Mastomys, which can be used in conjunction with RepeatMasker annotations. and these data presented
Load more

Recommended publications
  • Trim5o Requires Ube2w to Anchor Lys63-Linked Ubiquitin Chains And
    Article TRIM5a requires Ube2W to anchor Lys63-linked ubiquitin chains and restrict reverse transcription Adam J Fletcher1,†,§, Devin E Christensen2,§, Chad Nelson2, Choon Ping Tan1, Torsten Schaller1,‡, Paul J Lehner3, Wesley I Sundquist2 & Greg J Towers1,* Abstract followed by variable protein interaction domain(s). Although TRIM proteins can have wide-ranging biological roles, anti-pathogen TRIM5a is an antiviral, cytoplasmic, E3 ubiquitin (Ub) ligase that defense functions are common (Nisole et al, 2005; McNab et al, assembles on incoming retroviral capsids and induces their prema- 2011). The expression of many TRIM proteins is induced by type I ture dissociation. It inhibits reverse transcription of the viral interferons, and several have been shown to manipulate immune genome and can also synthesize unanchored polyubiquitin (poly- signaling pathways by ubiquitinating signal transducing proteins, Ub) chains to stimulate innate immune responses. Here, we show such as TRIM23, TRIM25, and TRIM56 (Gack et al, 2007; Arimoto that TRIM5a employs the E2 Ub-conjugating enzyme Ube2Wto et al, 2010; Tsuchida et al, 2010). Certain TRIM proteins, including anchor the Lys63-linked polyUb chains in a process of TRIM5a TRIM5a (Stremlau et al, 2004), TRIM21 (Mallery et al, 2010), and auto-ubiquitination. Chain anchoring is initiated, in cells and TRIM56 (Wang et al, 2011), have also been shown to target viral in vitro, through Ube2W-catalyzed monoubiquitination of TRIM5a. replication specifically. An emerging theme is that antiviral TRIM This modification serves as a substrate for the elongation of proteins both inhibit viral infection and initiate innate immune anchored Lys63-linked polyUb chains, catalyzed by the heterodi- signaling cascades that lead to inflammatory cytokine production meric E2 enzyme Ube2N/Ube2V2.
    [Show full text]
  • Trim5alpha Restricts Flavivirus Replication by Targeting the Viral Protease for Proteasomal Degradation
    University of Massachusetts Medical School eScholarship@UMMS Program in Molecular Medicine Publications and Presentations Program in Molecular Medicine 2019-06-11 TRIM5alpha Restricts Flavivirus Replication by Targeting the Viral Protease for Proteasomal Degradation Abhilash I. Chiramel National Institute of Allergy and Infectious Diseases Et al. Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/pmm_pp Part of the Amino Acids, Peptides, and Proteins Commons, Biochemistry Commons, Enzymes and Coenzymes Commons, Immunology and Infectious Disease Commons, Molecular Biology Commons, Molecular Genetics Commons, and the Virology Commons Repository Citation Chiramel AI, Meyerson NR, McNally KL, Broeckel RM, Montoya VR, Mendez-Solis O, Robertson SJ, Sturdevant GL, Lubick KJ, Nair V, Youseff BH, Ireland RM, Bosio CM, Kim K, Luban J, Hirsch VM, Taylor RT, Bouamr F, Sawyer SL, Best SM. (2019). TRIM5alpha Restricts Flavivirus Replication by Targeting the Viral Protease for Proteasomal Degradation. Program in Molecular Medicine Publications and Presentations. https://doi.org/10.1016/j.celrep.2019.05.040. Retrieved from https://escholarship.umassmed.edu/ pmm_pp/97 Creative Commons License This work is licensed under a Creative Commons Attribution 4.0 License. This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in Program in Molecular Medicine Publications and Presentations by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. Article TRIM5a Restricts Flavivirus Replication by Targeting the Viral Protease for Proteasomal Degradation Graphical Abstract Authors Abhilash I. Chiramel, Nicholas R. Meyerson, Kristin L. McNally, ..., Fadila Bouamr, Sara L.
    [Show full text]
  • Implication of Trim5alpha and Trimcyp in Interferon-Induced Anti
    Implication of TRIM5alpha and TRIMCyp in interferon-induced anti-retroviral restriction activities Laëtitia Carthagéna, Mélanie Parise, Mathieu Ringeard, Mounira Chelbi-Alix, Uriel Hazan, Sébastien Nisole To cite this version: Laëtitia Carthagéna, Mélanie Parise, Mathieu Ringeard, Mounira Chelbi-Alix, Uriel Hazan, et al.. Implication of TRIM5alpha and TRIMCyp in interferon-induced anti-retroviral restriction activities. Retrovirology, BioMed Central, 2008, 5 (1), pp.59. 10.1186/1742-4690-5-59. hal-02503964 HAL Id: hal-02503964 https://hal.archives-ouvertes.fr/hal-02503964 Submitted on 10 Mar 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Retrovirology BioMed Central Research Open Access Implication of TRIMalpha and TRIMCyp in interferon-induced anti-retroviral restriction activities Laetitia Carthagena1,2, Mélanie C Parise1,2, Mathieu Ringeard1,2, Mounira K Chelbi-Alix3, Uriel Hazan1,2,4 and Sébastien Nisole*1,2,4 Address: 1Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Département des Maladies Infectieuses, 22 rue Méchain, 75014,
    [Show full text]
  • Restriction of XMRV Infection
    Restriction of XMRV infection Kate Bishop National Institute for Medical Research 7th September 2010 Presented at the 1st Intl. Workshop on XMRV 7-8 September 2010, Bethesda USA Retroviral restriction factors Cell autonomous inhibitors of retroviral replication Inhibit a wide range of retro (and other) viruses, including MLVs Usually some species specificity - thought to influence zoonotic transmission and pathogenicity of infection Expressed in haematopoietic cells Four families: Fv1 (only in mice) Lilly, 1970; Best et al. 1996 APOBEC proteins Sheehy et al. 2002 TRIM5alpha/TRIMCyp Stremlau et al. 2004 Tetherin Neil et al. 2008; Van Damme et al. 2008 Presented at the 1st Intl. Workshop on XMRV 7-8 September 2010, Bethesda USA Blocks to the life cycle of a retrovirus 1. Binding 2. Fusion and 10. maturation entry TRIM5 7. Translation 3. Uncoating RTC Reverse transcription APOBEC3G Trafficking Fv1 8. Assembly PIC 4. Nuclear entry 6. Transcription 5. Integration 9. Budding provirus gag pol env Presented at the 1st Intl. Workshop on XMRV 7-8 September 2010, Bethesda USA APOBEC proteins Presented at the 1st Intl. Workshop on XMRV 7-8 September 2010, Bethesda USA The human family of APOBEC cytidine deaminases name function APOBEC1 apoB mRNA AID Antibody diversification (SHM & CSR) APOBEC2 APOBEC3A APOBEC3B anti-viral APOBEC3C APOBEC3D/E anti-viral APOBEC3F anti-viral APOBEC3G anti-viral APOBEC3H APOBEC4 cytidine deaminase cytidine deaminase motif motif Presented at the 1st Intl. Workshop on XMRV 7-8 September 2010, Bethesda USA APOBEC3G/3F proteins Highly expressed in leukocytes (T-cells, B-cells, monocyte), testis and ovary Protein expression upregulated by IFN in macrophage and dendritic cells but not in T-cells Most lentiviruses have a Vif protein that overcomes the APOBEC3G/3F of their host.
    [Show full text]
  • Expression Analysis of LEDGF/P75, APOBEC3G, Trim5alpha, and Tetherin in a Senegalese Cohort of HIV- 1-Exposed Seronegative Individuals
    Expression Analysis of LEDGF/p75, APOBEC3G, TRIM5alpha, and Tetherin in a Senegalese Cohort of HIV- 1-Exposed Seronegative Individuals Kim Mous1,2, Wim Jennes2, Makhtar Camara3, Moussa Seydi4,Ge´raldine Daneau2, Souleymane Mboup3, Luc Kestens2, Xaveer Van Ostade1* 1 Laboratory for Proteinscience, Proteomics and Epigenetic Signaling, Department of Biomedical Sciences, University of Antwerp, Wilrijk, Belgium, 2 Laboratory of Immunology, Department of Microbiology, Institute of Tropical Medicine, Antwerp, Belgium, 3 Laboratory of Immunology, Department of Bacteriology-Virology, Centre Hospitalier Universitaire Le Dantec, Cheikh Anta Diop University, Dakar, Senegal, 4 Department of Infectious Diseases, Centre Hospitalier Universitaire Fann, Cheikh Anta Diop University, Dakar, Senegal Abstract Background: HIV-1 replication depends on a delicate balance between cellular co-factors and antiviral restriction factors. Lens epithelium-derived growth factor (LEDGF/p75) benefits HIV, whereas apolipoprotein B mRNA-editing catalytic polypeptide-like 3G (APOBEC3G), tripartite motif 5alpha (TRIM5a), and tetherin exert anti-HIV activity. Expression levels of these proteins possibly contribute to HIV-1 resistance in HIV-1-exposed populations. Methodology/Principal Findings: We used real-time PCR and flow cytometry to study mRNA and protein levels respectively in PBMC and PBMC subsets. We observed significantly reduced LEDGF/p75 protein levels in CD4+ lymphocytes of HIV-1- exposed seronegative subjects relative to healthy controls, whereas we found no differences in APOBEC3G, TRIM5a,or tetherin expression. Untreated HIV-1-infected patients generally expressed higher mRNA and protein levels than healthy controls. Increased tetherin levels, in particular, correlated with markers of disease progression: directly with the viral load and T cell activation and inversely with the CD4 count.
    [Show full text]
  • The Control of Viral Infection by Tripartite Motif Proteins and Cyclophilin a Greg J Towers*
    Retrovirology BioMed Central Review Open Access The control of viral infection by tripartite motif proteins and cyclophilin A Greg J Towers* Address: MRC Centre for Medical Molecular Virology, Department of Infection, Royal Free and University College London Medical School, 46 Cleveland Street, London, W1T4JF, UK Email: Greg J Towers* - [email protected] * Corresponding author Published: 12 June 2007 Received: 3 May 2007 Accepted: 12 June 2007 Retrovirology 2007, 4:40 doi:10.1186/1742-4690-4-40 This article is available from: http://www.retrovirology.com/content/4/1/40 © 2007 Towers; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract The control of retroviral infection by antiviral factors referred to as restriction factors has become an exciting area in infectious disease research. TRIM5α has emerged as an important restriction factor impacting on retroviral replication including HIV-1 replication in primates. TRIM5α has a tripartite motif comprising RING, B-Box and coiled coil domains. The antiviral α splice variant additionally encodes a B30.2 domain which is recruited to incoming viral cores and determines antiviral specificity. TRIM5 is ubiquitinylated and rapidly turned over by the proteasome in a RING dependent way. Protecting restricted virus from degradation, by inhibiting the proteasome, rescues DNA synthesis, but not infectivity, indicating that restriction of infectivity by TRIM5α does not depend on the proteasome but the early block to DNA synthesis is likely to be mediated by rapid degradation of the restricted cores.
    [Show full text]
  • S41467-019-12388-Y.Pdf
    ARTICLE https://doi.org/10.1038/s41467-019-12388-y OPEN A tri-ionic anchor mechanism drives Ube2N-specific recruitment and K63-chain ubiquitination in TRIM ligases Leo Kiss1,4, Jingwei Zeng 1,4, Claire F. Dickson1,2, Donna L. Mallery1, Ji-Chun Yang 1, Stephen H. McLaughlin 1, Andreas Boland1,3, David Neuhaus1,5 & Leo C. James1,5* 1234567890():,; The cytosolic antibody receptor TRIM21 possesses unique ubiquitination activity that drives broad-spectrum anti-pathogen targeting and underpins the protein depletion technology Trim-Away. This activity is dependent on formation of self-anchored, K63-linked ubiquitin chains by the heterodimeric E2 enzyme Ube2N/Ube2V2. Here we reveal how TRIM21 facilitates ubiquitin transfer and differentiates this E2 from other closely related enzymes. A tri-ionic motif provides optimally distributed anchor points that allow TRIM21 to wrap an Ube2N~Ub complex around its RING domain, locking the closed conformation and promoting ubiquitin discharge. Mutation of these anchor points inhibits ubiquitination with Ube2N/ Ube2V2, viral neutralization and immune signalling. We show that the same mechanism is employed by the anti-HIV restriction factor TRIM5 and identify spatially conserved ionic anchor points in other Ube2N-recruiting RING E3s. The tri-ionic motif is exclusively required for Ube2N but not Ube2D1 activity and provides a generic E2-specific catalysis mechanism for RING E3s. 1 Medical Research Council Laboratory of Molecular Biology, Cambridge, UK. 2Present address: University of New South Wales, Sydney, NSW, Australia. 3Present address: Department of Molecular Biology, Science III, University of Geneva, Geneva, Switzerland. 4These authors contributed equally: Leo Kiss, Jingwei Zeng. 5These authors jointly supervised: David Neuhaus, Leo C.
    [Show full text]
  • Role of Human Trim5α in Intrinsic Immunity
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE REVIEW ARTICLE published: 15 Marchprovided 2012 by Frontiers - Publisher Connector doi: 10.3389/fmicb.2012.00097 Role of humanTRIM5α in intrinsic immunity Emi E. Nakayama andTatsuo Shioda* Department of Viral Infections, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan Edited by: Human immunodeficiency virus (HIV) has a very narrow host range. HIV type 1 (HIV-1) Atsushi Koito, Kumamoto University, does not infect Old World monkeys, such as the rhesus monkey (Rh). Rh TRIM5α was Japan identified as a factor that confers resistance, intrinsic immunity, to HIV-1 infection. Unfor- Reviewed by: α α Elisa Vicenzi, San Raffaele Scientific tunately, human TRIM5 is almost powerless to restrict HIV-1. However, human TRIM5 Institute, Italy potently restricts N-tropic murine leukemia viruses (MLV) but not B-tropic MLV, indicating Akatsuki Saito, Kyoto University, that humanTRIM5α represents the restriction factor previously designated as Ref1.African Japan green monkey TRIM5α represents another restriction factor previously designated as Lv1, *Correspondence: which restricts both HIV-1 and simian immunodeficiency virus isolated from macaque Tatsuo Shioda, Department of Viral Infections, Research Institute for (SIVmac) infection. TRIM5 is a member of the tripartite motif family containing RING, B- Microbial Diseases, Osaka University, box2, and coiled-coil domains. The RING domain is frequently found in E3 ubiquitin ligase, 3-1, Yamada-oka, Suita, Osaka and TRIM5α is thought to degrade viral core via ubiquitin–proteasome-dependent and - 565-0871, Japan. independent pathways. The alpha isoform of TRIM5 has an additional C-terminal PRYSPRY e-mail: [email protected] domain, which is a determinant of species-specific retrovirus restriction by TRIM5α.On the other hand, the target regions of viral capsid protein (CA) are scattered on the surface of core.
    [Show full text]
  • Restriction of Retroviral Replication by Tetherin/BST-2
    Hindawi Publishing Corporation Molecular Biology International Volume 2012, Article ID 424768, 9 pages doi:10.1155/2012/424768 Review Article Restriction of Retroviral Replication by Tetherin/BST-2 Jason Hammonds, Jaang-Jiun Wang, and Paul Spearman Department of Pediatrics, Emory University and Children’s Healthcare of Atlanta, 2015 Uppergate Drive, Atlanta, GA 30322, USA Correspondence should be addressed to Paul Spearman, [email protected] Received 27 March 2012; Accepted 26 May 2012 Academic Editor: Abraham Brass Copyright © 2012 Jason Hammonds et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Tetherin/BST-2 is an important host restriction factor that limits the replication of HIV and other enveloped viruses. Tetherin is a type II membrane glycoprotein with a very unusual domain structure that allows it to engage budding virions and retain them on the plasma membrane of infected cells. Following the initial report identifying tetherin as the host cell factor targeted by the HIV-1 Vpu gene, knowledge of the molecular, structural, and cellular biology of tetherin has rapidly advanced. This paper summarizes the discovery and impact of tetherin biology on the HIV field, with a focus on recent advances in understanding its structure and function. The relevance of tetherin to replication and spread of other retroviruses is also reviewed. Tetherin is a unique host restriction factor that is likely to continue to provide new insights into host-virus interactions and illustrates well the varied ways by which host organisms defend against viral pathogens.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 8,835,617 B2 Luban Et Al
    US008835617B2 (12) United States Patent (10) Patent No.: US 8,835,617 B2 Luban et al. (45) Date of Patent: Sep. 16, 2014 (54) POLYNUCLEOTIDES ENCODINGA HUMAN 2007/01051 22 A1 5/2007 Ota et al. TRIM-CYPFUSION POLYPEPTIDE, 2007/O141679 A1 6/2007 Sodroski et al. 2007/O185O17 A1 8/2007 Aggarwal et al. COMPOSITIONS THEREOF, AND METHODS 2008/004.5454 A1 2/2008 Luban et al. OF USING SAME (75) Inventors: Jeremy Luban, New York, NY (US); FOREIGN PATENT DOCUMENTS Martha Neagu, Gaithersburg, MD (US) EP 336523 A1 10, 1989 (73) Assignee: The Trustees of Columbia University WO WO-9011092 A1 10, 1990 in the City of New York, New York, NY WO WO-2006/O14422 2, 2006 (US) OTHER PUBLICATIONS (*) Notice: Subject to any disclaimer, the term of this Brennan et al. TRIMCyp expression in Old World primates Macaca patent is extended or adjusted under 35 nemestrina and Macaca fascicularis. PNAS, Mar. 4, 2008, vol. 105, U.S.C. 154(b) by 429 days. No. 9, pp. 3569-3574.* (21) Appl. No.: 13/128,143 Liao et al. A novel fusion gene, TRIM5-Cyclophilin A in the pig tailed macaque determines its susceptibility to HIV-1 infection. (22) PCT Filed: Nov. 6, 2009 AIDS 2007, vol. 21, Suppl. 8, S19-S26.* (86). PCT No.: PCT/US2O09/063481 Extended European Search Report mailed Apr. 10, 2012 for Euro pean Application No. 09825443.6, filed Nov. 6, 2009 (9 pages). S371 (c)(1), Neagu et al., “Potent inhibition of HIV-1 by TRIM5-cyclophilin (2), (4) Date: Dec. 1, 2011 fusion proteins engineered from Human components.” The Journal of (87) PCT Pub.
    [Show full text]
  • Cyclophilins As Modulators of Viral Replication
    Viruses 2013, 5, 1684-1701; doi:10.3390/v5071684 OPEN ACCESS viruses ISSN 1999-4915 www.mdpi.com/journal/viruses Review Cyclophilins as Modulators of Viral Replication Stephen D. Frausto, Emily Lee and Hengli Tang * Department of Biological Science, The Florida State University, Tallahassee, FL 32306, USA; E-Mails: [email protected] (S.D.F); [email protected] (E.L.) * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-850-645-2402; Fax: +1-850-645-8447. Received: 22 May 2013; in revised form: 26 June 2013 / Accepted: 3 July 2013 / Published: 11 July 2013 Abstract: Cyclophilins are peptidyl‐prolyl cis/trans isomerases important in the proper folding of certain proteins. Mounting evidence supports varied roles of cyclophilins, either positive or negative, in the life cycles of diverse viruses, but the nature and mechanisms of these roles are yet to be defined. The potential for cyclophilins to serve as a drug target for antiviral therapy is evidenced by the success of non-immunosuppressive cyclophilin inhibitors (CPIs), including Alisporivir, in clinical trials targeting hepatitis C virus infection. In addition, as cyclophilins are implicated in the predisposition to, or severity of, various diseases, the ability to specifically and effectively modulate their function will prove increasingly useful for disease intervention. In this review, we will summarize the evidence of cyclophilins as key mediators of viral infection and prospective drug targets. Keywords: cyclosporin; HIV; HCV; cyclophilin 1. Introduction Unlike other infective agents, viruses do not encode a full complement of proteins that allow them to proliferate independent of the host.
    [Show full text]
  • Multiple Sites in the N-Terminal Half of Simian Immunodeficiency Virus
    Kono et al. Retrovirology 2010, 7:72 http://www.retrovirology.com/content/7/1/72 RESEARCH Open Access Multiple sites in the N-terminal half of simian immunodeficiency virus capsid protein contribute to evasion from rhesus monkey TRIM5a-mediated restriction Ken Kono1, Haihan Song1, Masaru Yokoyama2, Hironori Sato2, Tatsuo Shioda1, Emi E Nakayama1* Abstract Background: We previously reported that cynomolgus monkey (CM) TRIM5a could restrict human immunodeficiency virus type 2 (HIV-2) strains carrying a proline at the 120th position of the capsid protein (CA), but it failed to restrict those with a glutamine or an alanine. In contrast, rhesus monkey (Rh) TRIM5a could restrict all HIV-2 strains tested but not simian immunodeficiency virus isolated from macaque (SIVmac), despite its genetic similarity to HIV-2. Results: We attempted to identify the viral determinant of SIVmac evasion from Rh TRIM5a-mediated restriction using chimeric viruses formed between SIVmac239 and HIV-2 GH123 strains. Consistent with a previous study, chimeric viruses carrying the loop between a-helices 4 and 5 (L4/5) (from the 82nd to 99th amino acid residues) of HIV-2 CA were efficiently restricted by Rh TRIM5a. However, the corresponding loop of SIVmac239 CA alone (from the 81st to 97th amino acid residues) was not sufficient to evade Rh TRIM5a restriction in the HIV-2 background. A single glutamine-to-proline substitution at the 118th amino acid of SIVmac239 CA, corresponding to the 120th amino acid of HIV-2 GH123, also increased susceptibility to Rh TRIM5a, indicating that glutamine at the 118th of SIVmac239 CA is necessary to evade Rh TRIM5a.
    [Show full text]