Human endogenous retroviruses (HERV) and non-HERV viruses incorporated into the human genome and their role in the development of autoimmune diseases

ABSTRACT The human genome harbors numerous distinct families of so-called human endogenous retroviruses (HERV) which are remnants of exogenous retroviruses that entered the germ line millions of years ago. We describe here the hitherto little-characterized betaretrovirus HERV-K(HML-5) family (named HERVK22 in Repbase) in greater detail. Out of 139 proviruses, only a few loci represent full-length proviruses, and many lack gag protease and/or env gene regions. We generated a consensus sequence from multiple alignment of 62 HML-5 loci that displays open reading frames for the four major retroviral proteins. Four HML-5 long terminal repeat (LTR) subfamilies were identified that are associated with monophyletic proviral bodies, implying different evolution of HML-5 LTRs and genes. Sequence analysis indicated that the proviruses formed approximately 55 million years ago. Accordingly, HML-5 proviral sequences were detected in Old World and New World primates but not in prosimians. No recent activity is associated with this HERV family. We also conclude that the HML-5 consensus sequence primer binding site is identical to methionine tRNA. Therefore, the family should be designated HERV-M. Our study provides important insights into the structure and evolution of the oldest betaretrovirus in the primate genome known to date.

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‘There and back again’: revisiting the pathophysiological roles of human endogenous retroviruses in the post-genomic era

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2012.0504 ◽

2013 ◽

Vol 368 (1626) ◽

pp. 20120504 ◽

Cited By ~ 45

Author(s):

Gkikas Magiorkinis ◽

Robert Belshaw ◽

Aris Katzourakis

Keyword(s):

Human Genome ◽

High Throughput Sequencing ◽

Immune Escape ◽

Genomic Sequence ◽

Sequence Data ◽

Endogenous Retroviruses ◽

Human Endogenous Retroviruses ◽

The Past ◽

Sequencing Technologies ◽

Research Questions

Almost 8% of the human genome comprises endogenous retroviruses (ERVs). While they have been shown to cause specific pathologies in animals, such as cancer, their association with disease in humans remains controversial. The limited evidence is partly due to the physical and bioethical restrictions surrounding the study of transposons in humans, coupled with the major experimental and bioinformatics challenges surrounding the association of ERVs with disease in general. Two biotechnological landmarks of the past decade provide us with unprecedented research artillery: (i) the ultra-fine sequencing of the human genome and (ii) the emergence of high-throughput sequencing technologies. Here, we critically assemble research about potential pathologies of ERVs in humans. We argue that the time is right to revisit the long-standing questions of human ERV pathogenesis within a robust and carefully structured framework that makes full use of genomic sequence data. We also pose two thought-provoking research questions on potential pathophysiological roles of ERVs with respect to immune escape and regulation.

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Human Endogenous Retrovirus HERV-K14 Families: Status, Variants, Evolution, and Mobilization of Other Cellular Sequences

Journal of Virology ◽

10.1128/jvi.79.5.2941-2949.2005 ◽

2005 ◽

Vol 79 (5) ◽

pp. 2941-2949 ◽

Cited By ~ 20

Author(s):

Aline Flockerzi ◽

Stefan Burkhardt ◽

Werner Schempp ◽

Eckart Meese ◽

Jens Mayer

Keyword(s):

Human Genome ◽

Germ Line ◽

Endogenous Retrovirus ◽

Endogenous Retroviruses ◽

Human Endogenous Retrovirus ◽

Long Terminal Repeats ◽

Essential Information ◽

Human Endogenous Retroviruses ◽

Consensus Sequences

ABSTRACT The human genome harbors many distinct families of human endogenous retroviruses (HERVs) that stem from exogenous retroviruses that infected the germ line millions of years ago. Many HERV families remain to be investigated. We report in the present study the detailed characterization of the HERV-K14I and HERV-K14CI families as they are represented in the human genome. Most of the 68 HERV-K14I and 23 HERV-K14CI proviruses are severely mutated, frequently displaying uniform deletions of retroviral genes and long terminal repeats (LTRs). Both HERV families entered the germ line ∼39 million years ago, as evidenced by homologous sequences in hominoids and Old World primates and calculation of evolutionary ages based on a molecular clock. Proviruses of both families were formed during a brief period. A majority of HERV-K14CI proviruses on the Y chromosome mimic a higher evolutionary age, showing that LTR-LTR divergence data can indicate false ages. Fully translatable consensus sequences encoding major retroviral proteins were generated. Most HERV-K14I loci lack an env gene and are structurally reminiscent of LTR retrotransposons. A minority of HERV-K14I variants display an env gene. HERV-K14I proviruses are associated with three distinct LTR families, while HERV-K14CI is associated with a single LTR family. Hybrid proviruses consisting of HERV-K14I and HERV-W sequences that appear to have produced provirus progeny in the genome were detected. Several HERV-K14I proviruses harbor TRPC6 mRNA portions, exemplifying mobilization of cellular transcripts by HERVs. Our analysis contributes essential information on two more HERV families and on the biology of HERV sequences in general.

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Role of Human Endogenous Retroviruses in Lymphoma Pathogenesis and a Possible Biomarker of Disease

Blood ◽

10.1182/blood.v112.11.3751.3751 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3751-3751 ◽

Cited By ~ 2

Author(s):

Scott D. Gitlin ◽

Rafael Contreras- Galindo ◽

Mark H. Kaplan ◽

David M. Markovitz

Keyword(s):

Human Genome ◽

Cell Lines ◽

Endogenous Retroviruses ◽

Human Endogenous Retrovirus ◽

Hiv Positive ◽

Human Endogenous Retroviruses ◽

Viral Expression ◽

Very High

Abstract Actively replicating retroviruses entered hominid species millions of years ago and through mutations preventing replication now exist as 8% of the human genome. Active retroviral particles and antigens from the supposedly dormant human endogenous retrovirus, HERV-K (HML2), have been identified in several cancer cell lines. We have recently demonstrated very high RNA titers of HERV-K (HML2) in the plasma of HIV positive individuals by nucleic acid sequence-based amplification (NASBA) and RT-PCR. We now demonstrate very high HERV-K (HML2) RNA titers in the plasma of patients with HIV positive and HIV negative non-Hodgkin lymphoma (NHL) and in Hodgkin Disease (HD), but not in normal individuals. Different copies of HERV-K (HML-2) present throughout the human genome exist as Type 1 viruses which encode a new oncoprotein, NP9, or as Type 2 viruses which encode a functional envelope (env) and express the Rec oncoprotein. Both Types 1 and 2 viruses appear in NHLs but only Type 1 appears in the plasma of those with HD. HERV-K (HML2) Env and Gag proteins, Env and Gag RNA, and Reverse Transcriptase (RT) activity are isolated from patients with a variety of NHLs, but not in normal controls or in patients with non-malignant diseases. Viral titers dramatically decrease, up to an approximately 7.5 log drop, when patients with NHL or HD go into remission following treatment. To further establish the presence of functional viruses in NHL and HD, immuno-gold electron microscopy allowed demonstration of HERV-K (HML2) particles in the plasma of lymphoma patients. Preliminary analysis of the effect of antiretroviral agents on cell lines infected with HERV-K (HML2) demonstrate a drug class-specific reduction in viral expression at drug concentration levels that range from 0.125 – 1 mcg/mL. In conclusion, we have demonstrated evidence that human endogenous retroviruses are found in the plasma of patients with NHL and HD, suggesting that these viruses, previously presumed to be inactive, may play a role in lymphoma pathogenesis. The observation that viral expression parallels declines in disease activity with treatment of disease may allow use of HERV-K (HML2) expression as a biomarker of lymphoma activity. The role of the HERV-K (HML2)-encoded oncoproteins in disease pathogenesis is under study, as is the potential role of antiretroviral therapy for these malignancies.

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Are human endogenous retroviruses triggers of autoimmune diseases? Unveiling associations of three diseases and viral loci

Immunologic Research ◽

10.1007/s12026-015-8671-z ◽

2015 ◽

Vol 64 (1) ◽

pp. 55-63 ◽

Cited By ~ 23

Author(s):

Bjørn A. Nexø ◽

Palle Villesen ◽

Kari K. Nissen ◽

Hanne M. Lindegaard ◽

Peter Rossing ◽

...

Keyword(s):

Autoimmune Diseases ◽

Endogenous Retroviruses ◽

Human Endogenous Retroviruses

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Implication of Human Endogenous Retroviruses in the Development of Autoimmune Diseases

International Reviews of Immunology ◽

10.3109/08830185.2010.485333 ◽

2010 ◽

Vol 29 (4) ◽

pp. 351-370 ◽

Cited By ~ 61

Author(s):

Eva Balada ◽

Miquel Vilardell-Tarrés ◽

Josep Ordi-Ros

Keyword(s):

Autoimmune Diseases ◽

Endogenous Retroviruses ◽

Human Endogenous Retroviruses

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Contribution of type W human endogenous retroviruses to the human genome: characterization of HERV-W proviral insertions and processed pseudogenes

Retrovirology ◽

10.1186/s12977-016-0301-x ◽

2016 ◽

Vol 13 (1) ◽

Cited By ~ 31

Author(s):

Nicole Grandi ◽

Marta Cadeddu ◽

Jonas Blomberg ◽

Enzo Tramontano

Keyword(s):

Human Genome ◽

Endogenous Retroviruses ◽

Human Endogenous Retroviruses ◽

Genome Characterization ◽

Processed Pseudogenes

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The Roles of Human Endogenous Retroviruses (HERVs) in Inflammation

Kosin Medical Journal ◽

10.7180/kmj.2021.36.2.69 ◽

2021 ◽

Vol 36 (2) ◽

pp. 69-78

Author(s):

Eun-Ji Ko ◽

Hee-Jae Cha

Keyword(s):

Inflammatory Response ◽

Autoimmune Diseases ◽

Molecular Level ◽

Inflammatory Diseases ◽

Innate Immune ◽

Endogenous Retroviruses ◽

Human Endogenous Retroviruses ◽

Action Mechanisms ◽

Signaling Mechanisms ◽

Lateral Sclerosis

Human endogenous retroviruses (HERVs) are ancient, currently inactive, and non-infectious due to recombination, deletions, and mutations in the host genome. However, HERV-derived elements are involved in physiological phenomena including inflammatory response. In recent studies, HERV-derived elements were involved directly in various inflammatory diseases including autoimmune diseases such as rheumatoid arthritis (RA), multiple sclerosis, amyotrophic lateral sclerosis (ALS), and Sjogren’s syndrome. Regarding the involvement of HERV-derived elements in inflammation, two possible mechanisms have been proposed. First, HERV-derived elements cause nonspecific innate immune processes. Second, HERV-derived RNA or proteins might stimulate selective signaling mechanisms. However, it is unknown how silent HERV elements are activated in the inflammatory response and what factors and signaling mechanisms are involved with HERV-derived elements. In this review, we introduce HERV-related autoimmune diseases and propose the possible action mechanisms of HERV-derived elements in the inflammatory response at the molecular level.

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HIV-1 Rev interacts with HERV-K RcREs present in the human genome and promotes export of unspliced HERV-K proviral RNA

Retrovirology ◽

10.1186/s12977-019-0505-y ◽

2019 ◽

Vol 16 (1) ◽

Cited By ~ 3

Author(s):

Laurie R. Gray ◽

Rachel E. Jackson ◽

Patrick E. H. Jackson ◽

Stefan Bekiranov ◽

David Rekosh ◽

...

Keyword(s):

Human Genome ◽

Regulatory Protein ◽

Endogenous Retroviruses ◽

Hiv Replication ◽

Human Endogenous Retroviruses ◽

Cytoplasmic Rna ◽

Cellular Mrnas ◽

Bioinformatic Approaches ◽

Reporter Mrna ◽

Hiv 1

Abstract Background The HERV-K (HML-2) viruses are the youngest of the human endogenous retroviruses. They are present as several almost complete proviral copies and numerous fragments in the human genome. Many HERV-K proviruses express a regulatory protein Rec, which binds to an element present in HERV-K mRNAs called the RcRE. This interaction is necessary for the nucleo-cytoplasmic export and expression of HERV-K mRNAs that retain introns and plays a role analogous to that of Rev and the RRE in HIV replication. There are over 900 HERV-K RcREs distributed throughout the human genome. Thus, it was of interest to determine if Rev could functionally interact with selected RcRE elements that map either to HERV-K proviruses or human gene regions. This interaction would have the potential to alter the expression of both HERV-K mRNAs and cellular mRNAs during HIV-1 infection. Results In this study we employed a combination of RNAseq, bioinformatics and cell-based functional assays. Potential RcREs were identified through a number of bioinformatic approaches. They were then tested for their ability to promote export and translation of a reporter mRNA with a retained intron in conjunction with Rev or Rec. Some of the selected elements functioned well with either Rev, Rec or both, whereas some showed little or no function. Rev function on individual RcREs varied and was also dependent on the Rev sequence. We also performed RNAseq on total and cytoplasmic RNA isolated from SupT1 cells expressing HIV Rev, with or without Tat, or HERV-K Rec. Proviral mRNA from three HERV-K loci (4p16.1b, 22q11.23 and most significantly 3q12.3) accumulated in the cytoplasm in the presence of Rev or Tat and Rev, but not Rec. Consistent with this, the 3′ RcRE from 3q12.3 functioned well with HIV-Rev in our reporter assay. In contrast, this RcRE showed little or no function with Rec. Conclusions The HIV Rev protein can functionally interact with many RcREs present in the human genome, depending on the RcRE sequence, as well as the Rev sequence. This leads to export of some of the HERV-K proviral mRNAs and also has the potential to change the expression of non-viral genes.

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