Multiple Sclerosis Retrovirus Particles and Recombinant Envelope Trigger an Abnormal Immune Response in Vitro, by Inducing Polyclonal Vβ16 T-Lymphocyte Activation

Perron, Hervé; Jouvin‐Marche, Evelyne; Michel, M.; Ounanian-Paraz, A.; Camelo, Serge; Dumón, Analía Delina; Jolivet-Reynaud, Colette; Marcel, F.; Souillet, Y.; Borel, Eve; Gebuhrer, L.; Santoro, Lyse; Marcel, Sébastien; Seigneurin, J. M.; Marche, Patrice N.; Lafon, Monique

doi:10.1006/viro.2001.1045

Cited by 178 publications

(171 citation statements)

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“…A molecular clone would be instrumental in shedding some light on this issue. This is also true for other known particles of endogenous retroviral origin belonging mostly to the HERV-H and HERV-W families (45,46). Meanwhile, the formation of infectious HERV particles and their potential for transmission remain controversial open questions.…”

Section: Production Of Herv Particlesmentioning

confidence: 99%

Retroelements and the human genome: New perspectives on an old relation

Bannert

Kurth

2004

Proc. Natl. Acad. Sci. U.S.A.

468

423

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Retroelements constitute a large portion of our genomes. One class of these elements, the human endogenous retroviruses (HERVs), is comprised of remnants of ancient exogenous retroviruses that have gained access to the germ line. After integration, most proviruses have been the subject of numerous amplifications and have suffered extensive deletions and mutations. Nevertheless, HERV-derived transcripts and proteins have been detected in healthy and diseased human tissues, and HERV-K, the youngest, most conserved family, is able to form virus-like particles. Although it is generally accepted that the integration of retroelements can cause significant harm by disrupting or disregulating essential genes, the role of HERV expression in the etiology of malignancies and autoimmune and neurologic diseases remains controversial. In recent years, striking evidence has accumulated indicating that some proviral sequences and HERV proteins might even serve the needs of the host and are therefore under positive selection. The remarkable progress in the analysis of host genomes has brought to light the significant impact of HERVs and other retroelements on genetic variation, genome evolution, and gene regulation.A lmost half of the mammalian genome is derived from ancient transposable elements. The two general types, (DNA)-transposons and retroelements, often regarded as ''selfish DNA parasites or junk DNA,'' encompass Ϸ2.8% and 42.2% of the human genome, respectively (1, 2). This striking finding is one of the many insights from recent large-scale sequencing projects that have provided the most valuable information in this field since the initial discovery of mobile elements in 1956 by Barbara McClintock (3, 4). Whereas DNA-transposons amplify without an RNA intermediate, retroelements rely on an RNA transcript that is retrotranscribed by a reverse transcriptase before integration in the genome. Here, we briefly review the characteristics of retroelements, their present classification, and the available evidence for their biological significance and function in normal and pathological processes. The focus is on human endogenous retroviruses (HERVs), the remnants of ancient germ-cell infections. Although most of the HERV proviruses have undergone extensive deletions and mutations, some have retained ORFs coding for functional proteins. A few families, including the HERV-K (HML-2) group, have been shown to form viral particles (5, 6), and an apparently intact provirus has recently been discovered in a small fraction of the human population, indicating a very recent acquisition (5-7). Classification of RetroelementsRetroelements constitute 90% of the Ϸ3 million transposable elements present in the human genome (1). They are split into two large groups, the non-LTR and LTR elements (Fig. 1). Two of the non-LTR members are present in extremely high copy numbers in the mammalian germ line: the short interspersed elements (SINE) with the prominent Alu and MIR repeats and the long-terminal interspersed elements (LINE) containing the...

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Section: Production Of Herv Particlesmentioning

confidence: 99%

Retroelements and the human genome: New perspectives on an old relation

Bannert

Kurth

2004

Proc. Natl. Acad. Sci. U.S.A.

468

423

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“…HERV-W env can function as an envelope protein, form pseudotypes with human immunodeficiency virus type 1 (HIV-1) virions and confer tropism for CD4-negative cells [83]. HERV-W env may also act as a superantigen, causing Vβ16-specific T-cell expansions [84]. In turn, ERV expression may be induced by environmental signals and activation of the immune system.…”

Section: Immunomodulation By Ervmentioning

confidence: 99%

Molecular mimicry and immunomodulation by the HRES-1 endogenous retrovirus in SLE

et al. 2008

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Genetic and environmental factors are believed to influence development of systemic lupus erythematosus (SLE). Endogenous retroviruses (ERV) correspond to the integrated proviral form of infectious retroviruses, which are trapped within the genome due to mutations. ERV represent a key molecular link between the host genome and infectious viral particles. ERV-encoded proteins are recognized by antiviral immune responses and become targets of autoreactivity. Alternatively, ERV protein may influence cellular processes and the life cycle of infectious viruses. As examples, the HRES-1 human ERV encodes a 28-kDa nuclear autoantigen and a 24-kDa small GTP-ase, termed HRES-1/Rab4. HRES-1/p28 is a nuclear autoantigen recognized by crossreactive antiviral antibodies, while HRES-1/Rab4 regulates surface expression of CD4 and the transferrin receptor (TFR) through endosome recycling. Expression of HRES-1/Rab4 is induced by the tat gene of HIV-1, which in turn down-regulates expression of CD4 and susceptibility to reinfection by HIV-1. CD4 and the TFR play essential roles in formation of the immunological synapse (IS) during normal T-cell activation by a cognate MHC class II peptide complex. The key intracellular transducer of T-cell activation, Lck, is brought to the IS via binding to CD4. T-cell receptorζ (TCRζ) chain binds to the TFR. Abnormal T-cell responses in SLE have been associated with reduced lck and TCRζ chain levels. HRES-1 is centrally located on chromosome 1 at q42 relative to lupus-linked microsatellite markers and polymorphic HRES-1 alleles have been linked to the development of SLE. 1q42 is one of the three most common fragile sites in the human genome, and is inducible by DNA demethylation, a known mechanism of retroviral gene activation. Molecular mimicry and immunomodulation by a ERV, such as HRES-1, may contribute to self-reactivity and abnormal Tand B-cell functions in SLE. (Table I). HERVs are commonly designated as HERV followed by a single letter amino acid code corresponding to a tRNA. The 3′ terminus of tRNA is predicted to initiate reverse transcription by annealing to an 18 nucleotide long primer-binding site (PBS) at the 5′ LTR. While expression of murine ERV can lead to production of infectious virus and cause viremia, no production of infectious virion has been documented by HERV. High copy number of most ERV families makes it difficult to distinguish which members of a group are expressed. Although, no single provirus with intact LTRs and uninterrupted gag, pol, and env ORFs has been identified, the HERV-K ERV, as a family, has been shown to encode gag HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript the LTR region, is functionally analogous to the HIV-1 rev and HTLV-I/II rex proteins. HERV-K rev binds to both the nuclear export factor Crm1 and to a cis-acting viral RNA to activate nuclear export of unspliced RNAs [39]. Alternatively, the HERV-K LTR is also recognized by HIV-1 rev, suggesting a potential interaction between these exogeneous a...

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“…Secondly, the proposed pathogenic role for HERV may be based on the correlation of superantigen (Ag) expression from proviruses, such as a novel HERV, termed 'IDDMK (1, 2) 22' in IDDMK and MSRV/ HERV-W in multiple sclerosis. 17,18 Thirdly, the effect of HERVs may instead be at the level of cellular gene transcription. CD5 negatively regulates B-cell Ag receptor (BCR)-mediated signaling through its constitutive association 19 with SH2-containing phosphatase-1 (SHP-1).…”

Section: Cd5 Endogenous Retrovirus Y Renaudineau Et Almentioning

confidence: 99%

Characterization of the human CD5 endogenous retrovirus-E in B lymphocytes

Renaudineau¹,

Vallet²,

Dantec³

et al. 2005

Genes Immun

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All T lymphocytes and some B lymphocytes express CD5. This coreceptor is encoded by one gene that consists of 11 exons. We have previously described a B cell-specific alternative exon 1, leading to the synthesis of a protein, devoid of leader peptide, and, therefore, retained in the cytoplasm. The novel exon 1 originates from a human endogenous retrovirus (HERV) at a time interval between the divergence of New World monkeys from Old World monkeys, and prior to the divergence of humans from Old World monkeys. Based on sequence similarity to g-retroviruses, it was categorized as class I: based on the specificity of its primer binding site, it was allotted to the subclass E, and based on its location within the cd5 gene, named HERV-E.CD5. Alternative transcripts were detected in lymphoid organs including fetal liver (not adult liver), more particularly in CD5-negative cell surface B-1b than in CD5-positive cell surface B-1a, and not at all in B-2 cells. By alignment of 5 0 long terminal repeats, HERV-E.CD5 was distinguished from similar proviruses. This could be central to the regulation of membrane expression of CD5 in human B lymphocytes, and, thereby, to the strength of the B-cell antigen receptor signaling.

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Multiple Sclerosis Retrovirus Particles and Recombinant Envelope Trigger an Abnormal Immune Response in Vitro, by Inducing Polyclonal Vβ16 T-Lymphocyte Activation

Cited by 178 publications

References 50 publications

Retroelements and the human genome: New perspectives on an old relation

Retroelements and the human genome: New perspectives on an old relation

Molecular mimicry and immunomodulation by the HRES-1 endogenous retrovirus in SLE

Characterization of the human CD5 endogenous retrovirus-E in B lymphocytes

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