Endogenous human viruses

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Evidence for genomic rearrangements mediated by human endogenous retroviruses during primate evolution. Nature Genet. Sun, C. Sanchez-Valle, A. Tomlins, S. Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature , — Cohen, C. Endogenous retroviral LTRs as promoters for human genes: a critical assessment. Gene , — Keeping active endogenous retroviral-like elements in check: the epigenetic perspective.

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Alternatively, some HERVs may have been difficult to eliminate and thus persisted during evolution. Several possibilities are highlighted below. The product derived from the env gene of mammalian type C retroviruses possesses motifs—for example, the fusion peptide, leucine zipper protein, and immunosuppressive peptide ISP —that are essential for fusion and the infection of cells.

In brief, the precursor env product is cleaved into two components: a surface protein gp70 and a transmembrane protein p15E that contains an immunosuppressive region. Another endogenous retrovirus, HERV-W, has also been shown to encode a protein termed syncytin, which may have a role in placental morphogenesis. Mechanisms of conferring protection against a related viral agent may include retroviral receptor blockade by HERV products and interference of replication by antisense mRNA.

However, it is also possible that HERV peptides could prime an immune response to an undesirable agent. Intriguingly, cohorts of female sex workers in the Gambia and Kenya have been identified who remain uninfected and seronegative despite being repetitively exposed to HIV. Consequently in some cases previous exposure to HERV peptides could potentially immunise certain individuals, although this argument does not explain why some females seroconvert after a reduction in sex work.

Retroviral genes that have been integrated into the genome are bordered by short direct repeats of host DNA and LTR sequences of about — nucleotides. These LTRs can influence neighbouring genes because they may contain transcriptional regulatory elements such as enhancers, promoters, hormone responsive elements, and polyadenylation signals.

In addition, their location adjacent to MHC or T cell receptor genes and transactivation by helper viruses 7 warrants further research into their potential role in autoimmune diseases and cancer. The term retroelements describes any sequence that can replicate itself by a process involving reverse transcription, and includes HERVs, retrotransposons which mostly lack an env gene , retroposons, and retrosequences.

Retroposons and retrosequences are exemplified by long stretches of related sequences up to 6 kbp called LINES and very short interspersed repeat elements of about bp, respectively.

Thus far, from being a fixed, immutable structure, the genome of a eukaryotic cell can harbour many sequences that move from one site on a chromosome to a completely different position. This phenomenon of plasticity is considered important because it permits rapid changes in our genome that could not be afforded by mutations alone. Furthermore, retroelements may carry regulatory sequences such as enhancers and promoters to new sites in the genome and thus alter the expression of existing adjacent genes.

It is known that many HERVs possess premature stop codons and of course the RNA products of truncated genes may well be eliminated before protein translation. Interestingly, some aminoglycoside antibiotics appear to suppress stop codons in several organisms. Howard and colleagues 83 demonstrated this effect in cell cultures that expressed constructs carrying two different premature stop codons within the cystic fibrosis gene CFTR.

Treatment with antibiotic produced a full length CFTR: the physiological suppression of the premature stop codon was thought to result from a mispairing of an amino-acyl tRNA that successfully bound to a stop codon. The importance of this observation is that HERVs, despite possessing premature stop codons, may have the potential to produce truncated or full length products that are fundamental to the mechanisms of molecular mimicry, aberrant expression of products, and the stimulation of T cells through superantigen motifs.

This article has provided an overview of a complex topic that may have ramifications in host protection, cancer, and autoimmunity. Ultimately, are HERVs friends or foes? Their role in immunological homeostasis and perhaps protection against exogenous retroviruses is intriguing. Alternatively, HERV insertion mutation, molecular mimicry, superantigen motifs, and recombination with other viruses could be responsible for the development and pathology of disease.

An additional aspect is whether the presence of HERV peptides during ontogeny culminates with a hole in the immune repertoire. Human endogenous retroviruses HERVs make up part of our genome and represent footprints of previous retroviral infection.

HERVs possess a similar genomic organisation gag—pol—env to present day exogenous retroviruses but are not infectious. HERVs may be of benefit to the host but could also be harmful, and may be involved in certain autoimmune diseases and cancers. Clearly, there is a need for multicentre studies to ascertain firm associations between HERV s and autoimmune disease states and certain cancers. Transcription of individual HERVs or the coordinated expression of HERVs, although important, must be balanced against expression found in normal tissues.

In addition, there is a requirement for a panel of readily available antibody reagents for example, monoclonal antibodies, recombinant phage antibodies to determine retroviral products at the site of disease. No doubt the field of HERV research will continue to accelerate so that we can fully ascertain the consequences of renegade endogenous retroviruses and their transfer in xenotransplanation. National Center for Biotechnology Information , U.

Journal List Mol Pathol v. Mol Pathol. Author information Article notes Copyright and License information Disclaimer. Accepted Sep This article has been cited by other articles in PMC. Abstract Human endogenous retroviruses HERVs are a family of viruses within our genome with similarities to present day exogenous retroviruses.

Keywords: human endogenous retroviruses, cancer, autoimmunity. Open in a separate window. Figure 1. Figure 2. Figure 3. Figure 4. Figure 5. Immunosuppressive peptide The product derived from the env gene of mammalian type C retroviruses possesses motifs—for example, the fusion peptide, leucine zipper protein, and immunosuppressive peptide ISP —that are essential for fusion and the infection of cells.

Antiviral resistance Mechanisms of conferring protection against a related viral agent may include retroviral receptor blockade by HERV products and interference of replication by antisense mRNA. Long terminal repeats Retroviral genes that have been integrated into the genome are bordered by short direct repeats of host DNA and LTR sequences of about — nucleotides. Take home messages Human endogenous retroviruses HERVs make up part of our genome and represent footprints of previous retroviral infection HERVs possess a similar genomic organisation gag—pol—env to present day exogenous retroviruses but are not infectious The HERV-K superfamily represents one of the most active HERVs and is capable of producing retroviral particles HERVs may be of benefit to the host but could also be harmful, and may be involved in certain autoimmune diseases and cancers.

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Immunogenetics ; 42 : 41 — HERV-K: the biologically most active human endogenous retrovirus family. Curr Biol ; 9 : —8. Detection and cloning of new HTLV-related endogenous sequences in man. Nucleic Acids Res ; 17 : — Int J Oncol ; 12 : — Human endogenous retrovirus K expression of gag protein and detection of antibodies in patients with seminomas.

J Virol ; 69 : — Human trophoblast and choriocarcinoma expression of the growth factor pleiotrophin attributable to germ-line insertion of an endogenous retrovirus. Defective retrovirus insertion activates c-Ha-ras proto-oncogene in an MNU-induced rat mammary carcinoma.

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Serological identification of human tumor antigens. Curr Opin Immunol : 9 : — Properties of retrovirus-like particles produced by a human breast carcinoma cell line: immunological relationship with mouse mammary tumour virus proteins.

Human endogenous retrovirus expression and reverse transcriptase activity in the T47D mammary carcinoma cell line. J Virol ; 70 : —7.

Stimulation of expression of the human endogenous retrovirus genome by female steroid hormones in human breast cancer cell line T47D. J Virol ; 61 : — Pleiotrophin and midkine in normal development and tumour biology. Crit Rev Oncog ; 6 : —7.

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Arthritis Rheum ; 38 : — Immunohistochemical localization of HTLV-I p and prelated antigens in synovial joints of patients with rheumatoid arthritis. Am J Pathol ; : 1 —5. Polymerase chain reaction fails to incriminate exogenous retroviruses HTLV-I and HIV-1 in rheumatological diseases although a minority of sera cross-react with retroviral antigens.

Ann Rheum Dis ; 53 : — Absence of lentiviral and human T cell leukaemia viral sequences in patients with rheumatoid arthritis. Arthritis Rheum ; 37 : — Herrmann M , Kalden JR. PCR and reverse dot hybridisation for the detection of endogenous retroviral transcripts.

J Virol Methods ; 46 : — Retrovirus-associated rheumatic syndromes. Curr Opin Rheumatol ; 10 : — Lancet ; : Expression of sequence variants of endogenous retrovirus RGH in particle form in multiple sclerosis. Molecular characterization and placental expression of HERV-W, a new human endogenous retrovirus family.

J Virol ; 73 : — A human endogenous retroviral superantigen as candidate autoimmune gene in type I diabetes. Cell ; 90 : — Cytokine regulation of env gene expression of human endogenous retrovirus-R in human vascular endothelial cells.

Clin Immunol ; 93 : 75 — Retroviral superantigens and type 1 diabetes mellitus. Cell ; 95 : 9 — Development of insulin-dependent diabetes mellitus does not depend on specific expression of the human endogenous retrovirus HERV-K. Cell ; 95 : 11 — Nakagawa K , Harrison LC. The potential roles of endogenous retroviruses in autoimmunity.

Immunol Rev ; : — Endogenous retroviruses: potential etiologic agents in autoimmunity. UV light and HIV gene activation. Yet, we still have a long way to go before we get close to understanding what most of these viruses do exactly, or in fact what even most of them are. It has been estimated that the field of virology so far has only explored around 1 per cent of viral diversity in existence. Despite this, they occur through all parts of our body.

A study led by Dr Kei Sato from the University of Tokyo published in June found viruses in human tissues including the brain, blood, kidney and liver. They did this by cross-referencing RNA sequence data against existing libraries of viral genomes, but this meant that they could only account for the handful of well-known viruses that were already in those libraries.

For example, viruses can be transmitted by a very wide range of mechanisms. For some, called endogenous retroviruses, viral DNA passes directly between human cells because they are integrated into chromosomes. In fact, 8 per cent of our human genome is composed of these endogenous retroviruses. Now, lots of this DNA is thought to be derived from previous virus insertions and we have discovered that it is highly important for regulating the transcription of other genes.