Abstract
The gammaretroviral human endogenous retrovirus (HERV) families MRSV/HERV-W and HERV-H (including the closely related HERV-Fc1) are associated with an increased risk of multiple sclerosis (MS). Complete HERV sequences betray their endogenous retroviral origin, with open reading frames in gag, pro, pol and env being flanked by two long terminal repeats containing promoter and enhancer sequences with the capacity to regulate HERV transactivation and the activity of host genes in spite of endogenous epigenetic repression mechanisms. HERV virions, RNA, cDNA, Gag and Env, and antibodies to HERV transcriptional products, have variously been found in the blood and/or brain and/or cerebrospinal fluid of MS patients, with the HERV expression level being associated with disease status. Furthermore, some HERV-associated single nucleotide polymorphisms (SNPs), such as rs662139 T/C in a 3-kb region of Xq22.3 containing a HERV-W env locus, and rs391745, upstream of the HERV-Fc1 locus on the X chromosome, are associated with MS susceptibility, while a negative association has been reported with SNPs in the tripartite motif-containing (TRIM) protein-encoding genes TRIM5 and TRIM22. Factors affecting HERV transcription include immune activation and inflammation, since HERV promoter regions possess binding sites for related transcription factors; oxidative stress, with oxidation of guanine to 8-oxoguanine and conversion of cytosine to 5-hydroxymethylcytosine preventing binding of methyl groups transferred by DNA methyltransferases; oxidative stress also inhibits the activity of deacetylases, thereby favouring the acetylation of histone lysine residues favouring gene expression; interferon beta; natalizumab treatment; impaired epigenetic regulation; and the sex of patients.
Highlights
Human endogenous retroviruses (HERVs), which are derived from previous exogenous retroviral infections, together with ERV-like DNA sequences make up about 8% of the human genome, distributed at approximately 700,000 different loci [1]
The matter was apparently settled by evidence supplied by Laufer and colleagues, who supplied evidence which suggested that all listed MSRV env sequences originated at HERV-W env Xq22.3 [52]; known HERV-W env loci or recombinations among them most likely involving the HERV-W env locus are located on chromosome Xq22.3, which rather argued for the creation of the MSRV virion by in vitro recombination events during polymerase chain reaction (PCR) [52]
While this single nucleotide polymorphisms (SNPs) could be responsible for increasing MRSV transcription, the increase in multiple sclerosis (MS) risk associated with the presence of rs662139 T/C could be secondary to an increase in inflammation, oxidative stress and localised DNA demethylation secondary to changes in activity in immune function genes, miRNAS or L1 sequences involved in the pathogenesis and/or pathophysiology of MS
Summary
Human endogenous retroviruses (HERVs), which are derived from previous exogenous retroviral infections, together with ERV-like DNA sequences make up about 8% of the human genome, distributed at approximately 700,000 different loci [1]. HERVs and their LTRs can provide promoters (alternative, sometimes bidirectional), enhancers, repressors, poly(A) signals and alternative splicing sites for human gene transcripts [12, 13]. HERV proviral sequences modulate the activity of nearby genes and have the capacity to regulate the genomic regulatory landscape via a number of mechanisms such as providing transcription factor binding sites [14, 15]. HERV expression is curtailed in healthy individuals by epigenetic machinery including GC methylation [25–27], histone modifications and RNA silencing [28–30]. Despite this level of epigenetic repression, HERVs continue to be expressed in the periphery and in the brain [30–34]. HERVactivity may impact on the diseases by the expression of RNA, cDNA, functional immunogenic proteins, superantigens and abnormal gene activation [9, 35]
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