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REVIEWS

Human RNA “Rumor” Viruses: the Search for Novel Human Retroviruses in Chronic Disease

Cécile Voisset, Robin A. Weiss, David J. Griffiths
Cécile Voisset
CNRS-UMR8161, Institut de Biologie de Lille et Institut Pasteur de Lille, Lille, France
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Robin A. Weiss
Division of Infection and Immunity, University College London, London, United Kingdom
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David J. Griffiths
Division of Virology, Moredun Research Institute, Penicuik, Midlothian, United Kingdom
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  • For correspondence: david.griffiths@moredun.ac.uk
DOI: 10.1128/MMBR.00033-07
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  • FIG. 1.
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    FIG. 1.

    Retrovirus structure and replication. (a) Genome organization. The RNA and DNA forms of a generalized retrovirus genome are shown with conserved features. R, repeated region at termini of RNA genome; U5 and U3, unique elements close to the 5′ and 3′ ends, respectively, of the RNA genome; PBS, primer binding site used for initiation of reverse transcription; Ψ, encapsidation signal; PPT, polypurine tract. All infectious retroviruses have at least one splice donor (SD) and one splice acceptor (SA) site used for expression of a spliced transcript encoding env; some retroviruses have additional splice sites. During reverse transcription, the LTR is formed, which contains gene promoter and enhancer elements. At least four genes are present in all infectious retroviruses, gag, pro, pol, and env. Retroviral proteins are synthesized as large polyprotein precursors and later cleaved into the mature viral proteins matrix (MA), capsid (CA), nucleocapsid (NC), protease (PR), reverse transcriptase (RT), and integrase (IN) and into-the-surface (SU) and transmembrane (TM) glycoproteins. Specific retroviruses encode additional proteins with specialized functions in the viral life cycle or pathogenesis. (b) Comparison of proviral structures of MLV and HTLV-1 showing arrangement of ORFs for viral genes. (Panels a and b are adapted from reference 345 with permission from Elsevier.) (c) Structure of a generalized retrovirus particle indicating virus capsid containing two copies of the RNA genome associated with NC protein, viral enzymes, and a cellular tRNA molecule. The capsid is contained within the viral lipid envelope, which is associated with the envelope glycoproteins. (d) Replication. Retroviruses infect their target cells by adsorption to one or more specific cell surface receptors. Binding leads to conformational changes in the envelope and receptor molecules that trigger fusion of the viral and cell membranes. Depending on the specific virus, this may occur at the plasma membrane or within endosomes following endocytosis. Fusion releases the viral core into the cytoplasm (uncoating), and reverse transcription is initiated, during which the single-stranded RNA genome is converted into a double-stranded DNA form. This DNA subsequently becomes integrated into the chromosomal DNA of the cell to form the provirus. The expression of viral genes and proteins requires the host cellular machinery for transcription and translation, although some retroviruses also encode proteins that can regulate these processes. The cellular specificity of expression is dependent on enhancer elements located in the LTR. Assembly of retroviral capsids occurs either in the cytoplasm prior to budding (betaretroviruses and spumaviruses) or at the plasma membrane concomitant with budding (all other retroviral genera). Once released, the retroviral protease is activated, and the viral polyproteins become cleaved into their mature forms. This maturation step is required for infectivity.

  • FIG. 2.
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    FIG. 2.

    Retrovirus-like particles described in diseased human tissues and cultured cells. (a) LM7 particles from leptomeningeal cells from MS induced by ICP0 protein of herpes simplex virus type 1. (Reprinted from reference 393 with permission of the publisher.) (b) Particles in cultured lymphocytes from MS. (Reprinted from reference 194 with permission from Elsevier.) (c) Particles in SS salivary gland (see arrows). (Reprinted from reference 540 with permission of the publisher.) (d) HICRV in ICL. Bar, 0.5 μm. (Reprinted from reference 193 with permission.) (e) Virus-like particles in human milk. (Reprinted from reference 429 by permission from Macmillan Publishers Ltd.) (f) Particles in PBC. (Reprinted from reference 538 with permission of the publisher. Copyright 2003 National Academy of Sciences, U.S.A.) (g) Particles in myeloproliferative disease. Bar, 100 nm. (Reprinted from reference 66 with permission from Elsevier.) (h) HERV-K in teratocarcinoma-derived cell lines labeled with gold anti-HERV-K Gag. (Reprinted from reference 61 with permission from Elsevier.)

  • FIG. 3.
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    FIG. 3.

    Electron micrographs of cell supernatants purified by sucrose density gradient centrifugation. Culture supernatants from EBV-transformed human B lymphocytes (a, b, d, and e) and HTLV-1-infected MT-2 cells (c and f) were concentrated by ultracentrifugation and then recentrifuged through a 10 to 60% sucrose density gradient. Fractions with a density typical of retroviruses (1.15 to 1.18 g/ml) were pooled, fixed in 2.5% paraformaldehyde-0.4% glutaraldehyde, and embedded in Epon resin. Ultrathin sections were stained with 1% uranyl acetate for 1 h and 1% lead citrate for 4 min and analyzed by transmission EM. Multiple vesicular particle-like structures can be observed. The origin of these structures is unclear, although they may be derived from cellular components such as polyribosomes, exosomes, and apoptotic blebs. Alternatively, because these cells were transformed with EBV, it is also possible that these structures are viral in origin (470). Panel f shows immunogold labeling of a Unicryl-embedded section with an anti-HTLV CA antiserum. Bar, 200 nm (C. Voisset, B. Mandrand, and G. Paranhos-Baccalà, unpublished data).

  • FIG. 4.
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    FIG. 4.

    Identification of novel viral sequences. A generalized scheme summarizing the approaches taken by a number of groups is shown (e.g., see references 9, 240, 500, 519, and 539). Sequence data can be generated experimentally or collected directly from expression sequence databases. Bullet points indicate alternative procedures at each stage. EST, expressed sequence tag.

  • FIG. 5.
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    FIG. 5.

    Scheme for recovery of viral nucleic acid from microarray spots. Hybridized viral sequences were physically scraped from a DNA microarray spot using a tungsten wire probe mounted on a micromanipulator, while the spots were visualized under fluorescence microscopy. Subsequently, the virus was identified by nucleic acid amplification, cloning, and sequencing. (Reprinted from reference 512 with permission.)

  • FIG. 6.
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    FIG. 6.

    Activation of HERV-K superantigen. Possible mechanisms for activation of a superantigen encoded by HERV-K18 on chromosome 1 (based on data from references 105, 219, 463, 471, 472, and 476). IgM, immunoglobulin M.

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  • TABLE 1.

    Confirmed infectious human retroviruses

    VirusYr identifiedAssociated disease(s)aReference
    HTLV-11980ATL, HAM/TSP, polymyositis, HAA399
    HTLV-21982HAM/TSPb242
    HIV-11983AIDS33
    HIV-21986AIDS101
    • ↵a HAA, HTLV-associated arthropathy.

    • ↵b The association of HTLV-2 with disease is tentative.

  • TABLE 2.

    Putative association of human diseases with retrovirusesa

    DiseaseReported evidenceRetrovirus(es) implicatedReference(s)
    Cancer
        Breast cancerEM, PCR, RT, FISH, AbMPMV, MMTV, HERV-K34, 132, 135, 137, 145, 287, 328, 514, 516, 517, 523, 545
        LymphomaPCRMPMV, HRV-5225, 260, 266, 350, 414
        Lung adenocarcinomaAgBetaretrovirus115, 116
        ThymomaEMUnknown16
        Ovarian carcinomaEM, PCR, Ab, AgHIV-like, HERVs405, 518
        MelanomaEM, PCR, RT, AbHERV-K25, 50, 81, 82, 223, 354, 431
        Myeloproliferative diseaseEM, PCR, RTHERV-K66, 69, 339
        Testicular tumorsEM, PCR, RT, AbHERV-K58, 60, 71, 118, 156, 174, 257, 404, 430
        Prostate cancerPCR, Ag, FISHXMRV125, 497
    Neurological disease
        SchizophreniaPCRHERV-W, HERV-K113, 246, 375, 521
        Motor neuron diseasePCR, RTHERV-W11, 371
        MSEM, PCR, RT, Ab, AgHERV-W, HERV-H13, 93-96, 98, 99, 194, 258, 385, 390, 391
        Chronic fatigue syndromeEM, RT“JHK-retrovirus”192
    Autoimmune and inflammatory
        RAEM, PCRHRV-5, HERVs67, 188, 356, 469
        SLEEM, PCR, AbHRV-5, HERVs, HIAPs67, 188, 212, 478, 480
        Mixed connective tissue diseaseNabHIV-related?127
        SSEM, PCR, RT, AgHIAPs, HRV-5161, 189, 444, 477, 540
        PBCEM, PCR, Ab, AgMMTV-like317, 318, 538
        Graves' diseaseEM, PCR, AbHFV, HIAP100, 235, 270
        IDDMPCR, RTHERV-K105, 463, 472
        PsoriasisEM, PCR, Ab, AgHERV-E43, 110, 214, 230, 335, 336
        Systemic sclerosisAbHIAP-I273
        Alopecia areataAbHIAP-I274
    Other
        ICLEM, Ab, RTHIAP-II, HICRV162, 193, 196
        OsteopetrosisEMUnknown68, 267
    • ↵a Ab, antiretroviral antibodies; Nab, neutralizing antibodies; Ag, retroviral antigen.

  • TABLE 3.

    Classification of retroviruses

    Subfamily and genusaPrevious nomenclatureSpecies infectedExample(s)
    Orthoretrovirinae
        AlpharetrovirusAvian C-type oncoretrovirusBirdsAvian leukosis viruses, Rous sarcoma virus
        BetaretrovirusB-type oncoretrovirusMiceMMTV
    D-type oncoretrovirusPrimatesMPMV
    SheepJSRV
        GammaretrovirusMammalian C-type oncoretrovirusMiceMLVs
    CatsFeline leukemia viruses
    PrimatesGibbon ape leukemia virus
    BirdsReticuloendotheliosis virus
        DeltaretrovirusC-type oncoretrovirusCattleBovine leukemia virus
    PrimatesHuman T-lymphotropic viruses
        EpsilonretrovirusNoneFishWalleye dermal sarcoma virus
        LentivirusLentivirusPrimatesHIV and SIV
    SheepMaedi/visna virus
    CatsFeline leukemia virus
    HorsesEquine infectious anemia virus
    Spumaretrovirinae
        SpumavirusFoamy virusPrimatesHFV and SFV
    CatsFeline foamy virus
    CattleBovine foamy virus
    • ↵a Refers to exogenous retroviruses only (286), but note that ERVs related to extant alpharetroviruses, betaretroviruses, gammaretroviruses, and spumaretroviruses are present in many vertebrate species.

  • TABLE 4.

    HERV proteins expressed in tissues and cultured cellsa

    HERV familyProtein(s) expressedTissueReferences
    HERV-KGag-Pro-PolTesticular cancer, melanomas, myeloproliferative disease, breast cancer, placenta30, 46, 61, 82, 294, 339, 354, 430, 488
    EnvGCTs, melanoma, ovarian cancer120, 488, 518
    Rec, Np9GCTs, melanoma17, 18, 58, 81, 118, 156, 305, 354, 541
    SAgEBV-infected B cells, IDDM(?)105, 219, 471, 472, 476
    ParticlesGCTs, melanoma, myeloproliferative disease46, 61, 82, 294, 339, 354
    HERV-WGagBrain, normal tissue, MS lesions, schizophrenia391, 426, 521
    Env (syncytin-1)Brain, placenta, breast cancer13, 52, 55, 56, 153, 309, 310, 333, 391
    Particlesb (MSRV, LM7)MS patient B cells and leptomeningeal cells387, 390, 393
    HERV-EEnvOvarian cancer, psoriasis, normal skin, interstitial lung disease43, 479, 518
    HERV-REnvPlacenta, ovarian cancer502, 518
    HERV-HIntact ORFs for Env proteinsUnknown but immunosuppressive in experimental systems118, 312
    Particlesb (RGH-2)Transformed lymphocyte cultures from MS patients94, 194
    HERV-FRDEnv (syncytin-2)Placenta53, 54, 307, 308
    HRES-1cGag-related proteinBrain, liver, T-lymphoblastoid cell lines28, 383
    • ↵a Many HERV families also transcribe RNA in a variety of tissues (for reviews, see references 29, 172, 498, and 529). GCT, germ cell tumor.

    • ↵b The identities of these RVLPs have not been demonstrated experimentally.

    • ↵c The retroviral origin of HRES-1 is disputed (492).

  • TABLE 5.

    Potential mechanisms for HERV-induced disease

    MechanismAgentReference(s)
    Direct action of HERV proteinHERV-K Rec and Np918, 58, 117, 156
    HERV-K SAg219, 463, 471, 472, 476
    HERV-W Env13, 389, 420
    HERV-H Env312
    Autoimmune/immune responseHERV-K24, 60, 208, 404, 430
    HIAP161, 235, 273, 274, 318, 477, 478
    Insertional mutagenesisaLINEs89, 334, 344
    Murine ERVs527, 536
    Modulation of cellularHERV-E271, 325, 435
        gene expressionHERV-L129
    Interaction withHERV-K219, 471, 472
        exogenous virusesHERV-W76, 77, 393
    • ↵a Insertional mutagenesis by HERVs has not been described, but analogous mutations have been reported for murine ERVs and for long interspersed nuclear elements (LINEs) in humans.

  • TABLE 6.

    Degenerate PCR primers based on conserved motifs in retroviruses

    Protein(s)Motif(s)aGenusReference(s)
    RTLPQG, YXDDAll106, 124, 189, 214, 251, 301, 421, 440, 447
    RTSeveralLentivirus122
    RT (nested primers)SeveralAll284
    RT (heminested primers)LPQG, YXDDAll246, 385, 493
    PRDTGBetaretrovirus189
    PR, RTGRD, LPQGBetaretrovirus324
    PR, RTDTG, YXDDAll207, 380, 491
    PR, RTDTGA, VLPQG, YMDDAll381
    IN (nested primers)SeveralSpumaretrovirus436
    NC, INSeveralBetaretrovirus190
    PolSeveralDeltaretrovirus128, 394
    Pol (nested primers)SeveralLentivirus169
    Gag, PolSeveralSpumavirus (of primates)47, 73
    Gag, PolSeveralNon-HERV80
    Gag, PolSeveralBetaretrovirus (of primates)282
    • ↵a Consensus peptide motifs used.

  • TABLE 7.

    Hill's criteria for causation in diseasea

    CriterionAssociation
    Strength of associationWhat is the relative increased risk in disease after exposure to virus?
    Consistency of associationHow reproducible are the data with different methods and by different laboratories, etc.?
    Specificity of associationIs the disease unique to exposure to virus?
    TemporalityDoes disease follow exposure?
    Biological gradientDoes an increased dose of virus lead to more rapid onset or more severe symptoms?
    PlausibilityIs a causal relationship biologically plausible?
    CoherenceIs a relationship compatible with present knowledge of the disease?
    ExperimentDoes experimental manipulation or intervention affect disease outcome, e.g., therapy?
    AnalogyIs there a comparable association with related virus or disease, e.g., animal models?
    • ↵a Adapted from reference 152 with permission. See also reference 210.

  • TABLE 8.

    Candidate retroviruses in human disease assessed by Hill's criteriaa

    Causal criterionAssociation
    HIV-1 and AIDSHTLV-I and ATLMMTV and breast cancerHERV-W and MSHERV-K18 and IDDMHIAP and SS/ICLHRV-5 and RA, SLE, lymphomaXMRV
    Strength of associationYYNNDbNDbNDNND
    Consistency of associationYYNYcNNDNND
    Specificity of associationYNNNbNbNNND
    TemporalityYYNDYbYbNDNDND
    Biological gradientYYNDNDNDNDNDY
    PlausibilityYYNNDNDNDNDND
    CoherenceYYNNDNDNDNDY
    ExperimentationYYNDNDNDNDNDND
    AnalogyYYYYYYYY
    • ↵a Y, yes; N, no; ND, not done/insufficient data.

    • ↵b Because endogenous.

    • ↵c For the Env protein.

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Human RNA “Rumor” Viruses: the Search for Novel Human Retroviruses in Chronic Disease
Cécile Voisset, Robin A. Weiss, David J. Griffiths
Microbiology and Molecular Biology Reviews Mar 2008, 72 (1) 157-196; DOI: 10.1128/MMBR.00033-07

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Human RNA “Rumor” Viruses: the Search for Novel Human Retroviruses in Chronic Disease
Cécile Voisset, Robin A. Weiss, David J. Griffiths
Microbiology and Molecular Biology Reviews Mar 2008, 72 (1) 157-196; DOI: 10.1128/MMBR.00033-07
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  • Top
  • Article
    • SUMMARY
    • INTRODUCTION
    • STRUCTURE AND REPLICATION OF RETROVIRUSES
    • HUMAN ENDOGENOUS RETROVIRUSES: CONFOUNDING FACTORS FOR HUMAN RETROVIRUS DISCOVERY
    • HUMAN DISEASES WITH SUSPECTED RETROVIRAL ETIOLOGY
    • LABORATORY METHODS FOR IDENTIFYING RETROVIRAL INFECTIONS
    • SPECIFIC CANDIDATE HUMAN RETROVIRUSES
    • HUMAN INFECTION WITH SIMIAN RETROVIRUSES
    • HUMAN RNA “RUMOR” VIRUSES: PROVING CAUSATION
    • CONCLUDING REMARKS
    • ACKNOWLEDGMENTS
    • REFERENCES
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