The human virome (representing human viral communities) presents greater technical challenges (1) for identification and enumeration compared to the microbiome.
Technical difficulties with characterizing the human virome
- We identify bacteria in the human microbiome using conserved genomic sequences (16S rRNA). Lacking such conserved genomic regions, viral genomic sequences from human samples are compared to known virus reference sequence databases. Drawback is such databases don’t include sequences from novel viruses (2) while the human virome likely harbors as-yet-undiscovered viruses and viral relics.
- Viruses have small genomes, and are proportionally fewer compared to bacteria. Thus, viral nucleic acids are proportionally minuscule in the total derived from human microbial communities. To detect them, we need to enrich viral nucleic acids before sequence analysis. In turn, enrichment methods could be unwittingly selective, bias against certain viruses, and lead to loss of low-abundance viruses (3).
The human virome constitutes viral communities all over the human body. They run the gamut from viral relics such as HERVs (Human Endogenous Retroviruses), retroviral genes internalized millions of years ago during evolution, to tissue-resident viruses such as CMV (Cytomegalovirus) in the respiratory tract. Contribution of these viral communities also runs the gamut from most essential such as HERV-W genes, necessary for placental development, to HERV-K, the most recent integrant, implicated in neurological diseases such as schizophrenia, cancers such as breast and prostate, and autoimmune diseases such as MS (multiple sclerosis), RA (rheumatoid arthritis) and SLE (systemic lupus erythematosus).
Figure 1 from 5
HERVs (Human Endogenous Retroviruses)
- Viral genetic material is either DNA or RNA. Retroviruses have RNA but use it to produce DNA, the reverse, ‘retro’, of the norm. When inserted into host DNA, this viral DNA replicates every time host DNA replicates. When retroviruses infect germline (eggs and sperm) cells, they acquire a vastly greater capacity to replicate. Now endogenous retroviruses (ERV), they are present not just in each and every cell of that host but also get passed on to each and every cell of the host’s descendants.
- ERVs represent 8% of the human genome (6).
- How do we know we harbor such retroviral relics? By their striking structural genomic similarity consisting of gag, pro, pol and env genes flanked by two identical-at-integration non-coding long terminal repeats (LTRs), which contain the signal for transcription initiation and regulation.
- Over evolutionary time (~35 million years), ERVs accumulated mutations (insertions, deletions, substitutions) and/or epigenetic modifications (for e.g., DNA methylation) at the same rate as the host genome (7, 8, 9, 10), rendering them non-functional, i.e. unable to produce infectious viral particles.
- Recombinations between the two flanking LTRs removed the internal coding region leaving a single LTR and inactivating ERVs, which are 10–100 times more numerous than their full length counterparts (11), and many of these insertions are fixed in the host population.
- To date, no active ERVs have been discovered in humans. The human genome has ~100,000 ERV loci resulting from proliferations of ~50 independent invasions of the genome from free-living (exogenous) retroviruses (12, 13).
Figure 2 from 14
HERV classification is still a work-in-progress. Magiorkinis et al (15) classify HERV families as the typical, HERV-T; the old, HERV-L; the abundant, HERV-H; the indispensable, HERV-W; the last but not the least, HERV-K.
- HERV-K(HML2) or HK2, the most recent, is the only ERV lineage to still replicate in the human population within the last few million years.
- ~1,000 HK2 loci in the human reference genome, apparently integrated over the last ~35 million years. Continuously replicating over this long period, most full-length integrated ERV loci (proviruses) converted to relics by recombination. Remainder acquired premature stop codons and/or frameshifts. All reference genome HK2 loci are therefore replication defective, and only 24 loci retain full-length open reading frames (ORFs) in at least one of their genes (16).
- RNA transcription and protein expression of HK2 and other ERVs are elevated in many cancers, some autoimmune/inflammatory diseases, and HIV infection, leading to a long and unresolved search for a causal role in disease (17, 18, 19). More recently, disease-associated elevation of HERV protein expression has driven research into their potential as immunotherapy targets for cancer and HIV treatment (20).
HERV-W, the indispensable HERVs in the Placenta: Genes Syncytins 1 and 2
- The emergence of placentation during evolution is fundamental to human evolution.
- Indispensable for human fetus growth, the placenta is composed of multiple unique cell types called extravillous and villous trophoblasts. The latter differentiate into multinucleated cells called syncytiotrophoblasts, which secrete human chorionic gonadotropin (hCG) and human placental lactogen (hPL), products that help optimize mother-fetus nutrient and hormone exchange.
- Viral relics in the form of specific HERVs are essential for placental development (14, 21, 22).
- Viruses were long suspected present in placenta with virus-like particles observed in human placenta (23, 24, 25, 26). These observations faded from memory until the discovery of the Syncytin genes in the late 1990s.
- Two Env proteins, Syncytin-1 and Syncytin-2 proteins, encoded by two different ERV loci, i.e., ERVW-1 and ERVFRD-1, located on chromosome 7 and 6, respectively, are expressed in the placenta. Independently co-opted numerous times among placental mammals and expressed in the placenta, these genes play a crucial role in the formation of the syncytiotrophoblast, a key function that sustains the highly dynamic and metabolically demanding placenta (27, 28, 29, 30, 31, 32, 33, 34, 35).
Figure 1 from 36.
– Viral genes like these may actually have been central in the emergence of placental mammals from egg-laying animals (29, 37, 38, 39, 40).
Box from 36.
- In vitro studies (41) and reduced expression in pre-eclampsia (42, 43, 44, 45, 46, 47, 48, 49) suggest these retroviral-origin genes are important in human placentation. Pre-eclampsia, ‘toxemia of pregnancy’, includes hypertension, liver and kidney toxicity, and if untreated, can lead to eclampsia, i.e. seizures, threatening the life of mother and child. These multiple, independent studies thus suggest that human placental syncytin expression is crucial for normal placental function and ensuing normal pregnancy.
- Mouse syncytin gene knockouts provide more definitive proof. Syncytin-1 knockout mouse: growth retardation, altered placental strcuture, death in utero (50). Syncytin-2 knockout mouse: impaired syncytiotrophoblasts (51).
- Serving a similar purpose in placentation of eutherian mammals, syncytin genes are thus a most extreme and powerful example of convergent evolution, having evolved independently multiple times through co-option of HERV genes.
HERVs in the brain: No definitive proof of disease causation. Lot of correlative data for neurological diseases,
Table 1 from 52.
especially for schizophrenia.
Tables 1 and 2 from 53
HERVs and cancer
How to be sure something causes cancer? Likely causes are so numerous ranging from genetic predisposition to numerous environmental factors that pinning one or few down as causative agents is akin to the proverbial needle in a haystack. In 1965 proposed the famous Hill’s criteria (54), essential in helping ascribe causality, as in the link between smoking and lung cancer. How does that pan out with HERVs (55, 56, 57)?
Consistency of association: HERVs consistently expressed in many tumors (breast, ovarian, lymphoma, melanoma, sarcoma, bladder, prostate).
Strength of association: HERVs rarely expressed in normal tissues.
Temporal association: Environmental factors as in exogenous such as chemicals, UV radiation, smoking, viruses, and endogenous as in hormones and cytokines help drive HERV expression.
Biological plausibility: no clear evidence yet.
Experimental evidence: no clear evidence yet in humans (some mouse model data exists).
Clearly work-in-progress.HERV-Breast Cancer link: 58, 59; HERV-Melanoma link: 60; HERV-prostate cancer link: 61.
HERVs and autoimmunity (62, 63): MS (multiple sclerosis; 64, 65), RA (rheumatoid arthritis: 66, 67), SLE (systemic lupus erythematosus: 68), Sjogren’s syndrome, Graves Disease.
- Association data; no causal data yet.
- Certain HERVs and herpes viruses associated with MS.
- Circulating anti-HERV antibodies present in >50% of SLE in some studies.
- Those with anti-HERV antibodies more likely to have active clinical SLE.
Location-wise identity of Viruses in Human body
- Stable over time (69), unsurprisingly healthy gut virome is influenced by diet (70).
- Abundance of food-related (plant) viruses (71).
- Eneteropathogenic viruses (72) found in both healthy and in those with GI tract illnesses (73).
- Novel bacteriophages encode genes for antibiotic resistance and bacterial metabolic pathways (69, 70, 74). More diverse in adults, much less so in a 1-week old infant stool sample (75). Clearly, we dynamically acquire a gut bacteriophage community over time.
- Novel viruses. Viruses from the new genus Gyrovirus in the Circoviridae family (76) are found in both chicken meat and human samples. Open questions: Do they replicate in humans, i.e. capable of cross-species transmission, or are they harmless?
- Diarrhea was associated with novel viruses such as astrovirus (77), cosavirus and bocavirus (78).
Persistent colonization by papillloma, polyoma, and circoviruses(79, 80). Innocuous for the most part. Exception is Merkel cell polyomavirus associated with severe skin carcinoma (81).
Human circulatory system
- Anelloviridae are ubiquitous in human populations (82, 83).
- An intriguing heart and lung transplant study (84) tracked circulating plasma virome months post-transplant, and found circulating virome changed with post-transplant treatment. Low dose of anti-viral (valganciclovir) and immunosuppressant (tacrolimus): Herpesvirales and Caudovirales dominate; high dose, Anelloviridae dominate.
Graphical Abstract from 84.
Flavivirus GBVC (or Hepatitis virus G), a surprising partner in human health, delays HIV disease progression (85).
- Influenza (flu), Corona and other less well-characterized viruses (86).
- Bocavirus found in both healthy and in those with respiratory tract illnesses (87).
- Bacteriophages: Cystic Fibrosis (CF) patients have bacteriophages similar to each other while those in healthy adults are unique to each individual (88). In this study, spouse of one CF patient and an asthmatic control shared some viral genomes found in CF patients. This suggests environment strongly influences human viral genome since shared environment was associated with shared viruses between spouses, and chronic pathologies that are very different, as CF and asthma are, could still lead to establishment of similar viral communities, perhaps because they both cause impaired airway clearance of microbes.
- CMV, a herpes virus, infects majority of the world’s population.
- In the US, ~60% prevalence in >6 years of age and ~>90% in >80 years of age in the years 1988-1994 (89).
- It’s usually, but not always, benign (90).
- Associated with immunosenescence (immune aging) in the elderly (91).
- CMV-schizophrenia link: In a study of >1000 subjects, 15% carried a particular benign variant of a gene involved in the stabilization of neuronal connections and in synaptic plasticity, essential to learning and memory. Carriers of this gene variant had fivefold increased probability of developing schizophrenia following maternal CMV infection (92).
- CMV-Flu link: CMV could help body fight off flu: CMV-seropositive young adults make stronger anti-flu antibody responses (93). Seropositive means they were likely exposed to CMV and generated an anti-CMV immune response, as revealed by presence of circulating anti-CMV antibodies. Relevance of this type of finding? The well-adjusted human super-organism is one where their mammalian and microbial components work in harmony to keep pathogens at bay.
- Flu-HERV link: The influenza virus may re-activate HERVs that are associated with neuroinflammation, and white matter and myelin degeneration (94).
- Such HERVs have been implicated in Bipolar disorder and Schizophrenia (95, 96).
- Canuti, M. “About Viruses, the Importance of Being Earnest.” Austin Virol and Retrovirology 1.1 (2014): 2. .
- Woolhouse ME, Howey R, Gaunt E, Reilly L, Chase-Topping M, Savill N. Temporal trends in the discovery of human viruses. Proc Biol Sci 2008;275:2111–5.
- Thurber RV, Haynes M, Breitbart M, Wegley L, Rohwer F. Laboratory procedures to generate viral metagenomes. Nat Protoc 2009;4:470–83.
- Delwart, Eric. “A roadmap to the human virome.” PLoS pathogens 9.2 (2013): e1003146.
- Wylie, Kristine M., George M. Weinstock, and Gregory A. Storch. “Emerging view of the human virome.” Translational Research 160.4 (2012): 283-290.
- Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, et al. (2001) Initial sequencing and analysis of the human genome. Nature 409: 860–921.
- Blikstad V, Benachenhou F, Sperber GO, Blomberg J (2008) Evolution of human endogenous retroviral sequences: a conceptual account. Cellular and Molecular Life Sciences 65: 3348–3365.
- Dewannieux, M.; Heidmann, T. Endogenous retroviruses: Acquisition, amplification and taming of genome invaders. Curr. Opin. Virol. 2013, 3, 646–656.
- Stoye, J.P. Studies of endogenous retroviruses reveal a continuing evolutionary saga. Nat. Rev. Microbiol. 2012, 10, 395–406.
- Magiorkinis, G.; Gifford, R.J.; Katzourakis, A.; de Ranter, J.; Belshaw, R. Env-less endogenous retroviruses are genomic superspreaders. Proc. Natl. Acad. Sci. USA 2012, 109, 7385–7390.
- Stoye JP (2001) Endogenous retroviruses: still active after all these years? Curr Biol 11: R914–916.
- Belshaw R, Pereira V, Katzourakis A, Talbot G, Pa?es J, Burt A, Tristem M. 2004. Long-term reinfection of the human genome by endogenous retroviruses. Proc. Natl. Acad. Sci. U. S. A. 101:4894 – 4899.
- Mayer J, Blomberg J, Seal RL. 2011. A revised nomenclature for transcribed human endogenous retroviral loci. Mobile DNA 2:7.
- Young, George R., Jonathan P. Stoye, and George Kassiotis. “Are human endogenous retroviruses pathogenic? An approach to testing the hypothesis.” Bioessays 35.9 (2013): 794-803.
- Magiorkinis, Gkikas, Robert Belshaw, and Aris Katzourakis. “‘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 368.1626 (2013): 20120504.
- Subramanian RP, Wildschutte JH, Russo C, Coffin JM. 2011. Identification, characterization, and comparative genomic distribution of the HERV-K (HML-2) group of human endogenous retroviruses. Retrovirology 8:90.
- Voisset C, Weiss RA, Griffiths DJ. 2008. Human RNA “rumor” viruses: the search for novel human retroviruses in chronic disease. Microbiol. Mol. Biol. Rev. 72:157–196.
- Young GR, Stoye JP, Kassiotis G. 2013. Are human endogenous retro- viruses pathogenic? An approach to testing the hypothesis. Bioessays 35: 794 – 803.
- Jern P, Coffin JM. 2008. Effects of retroviruses on host genome function. Annu. Rev. Genet. 42:709 –732.
- Marchi, Emanuele, et al. “Unfixed endogenous retroviral insertions in the human population.” Journal of virology 88.17 (2014): 9529-9537.
- Mangeney M, Renard M, Schlecht-Louf G, Bouallaga I, et al. 2007. Placental syncytins: genetic disjunction between the fusogenic and immunosuppressive activity of retroviral envelope proteins. Proc Natl Acad Sci USA 104: 20534–9.
- Dupressoir A, Lavialle C, Heidmann T. 2012. From ancestral infectious retroviruses to bona fide cellular genes: role of the captured syncytins in placentation. Placenta 33: 663–71.
- Kalter SS, Helmke RJ, Heberling RL, Panigel M, et al. 1973. Brief communication: C-type particles in normal human placentas. J Natl Cancer Inst 50: 1081–4.
- Vernon ML, McMahon JM, Hackett JJ. 1974. Additional evidence of type-C particles in human placentas. J Natl Cancer Inst 52: 987–9.
- Kalter SS, Heberling RL, Helmke RJ, Panigel M, Smith GC, Kraemer DC, Hellman A, Fowler AK, Strickland JE (1975) A comparative study on the presence of C-type viral particles in placentas from primates and other animals. Bibl Haematol 1975(40):391–40.
- Dirksen ER, Levy JA. 1977. Virus-like particles in placentas from normal individuals and patients with systemic lupus erythematosus. J Natl Cancer Inst 59: 1187–92.
- Blond, J.L.; Beseme, F.; Duret, L.; Bouton, O.; Bedin, F.; Perron, H.; Mandrand, B.; Mallet, F. Molecular characterization and placental expression of herv-w, a new human endogenous retrovirus family. J. Virol. 1999, 73, 1175–1185.
- Blond, J.L.; Lavillette, D.; Cheynet, V.; Bouton, O.; Oriol, G.; Chapel-Fernandes, S.; Mandrand, B.; Mallet, F.; Cosset, F.L. An envelope glycoprotein of the human endogenous retrovirus herv-w is expressed in the human placenta and fuses cells expressing the type d mammalian retrovirus receptor. J. Virol. 2000, 74, 3321–3329.
- Mi, S.; Lee, X.; Li, X.; Veldman, G.M.; Finnerty, H.; Racie, L.; LaVallie, E.; Tang, X.Y.; Edouard, P.; Howes, S.; et al. Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 2000, 403, 785–789.
- Frendo, J.L.; Olivier, D.; Cheynet, V.; Blond, J.L.; Bouton, O.; Vidaud, M.; Rabreau, M.; Evain-Brion, D.; Mallet, F. Direct involvement of herv-w env glycoprotein in human trophoblast cell fusion and differentiation. Mol. Cell. Biol. 2003, 23, 3566–3574.
- Blaise, S.; de Parseval, N.; Benit, L.; Heidmann, T. Genomewide screening for fusogenic human endogenous retrovirus envelopes identifies syncytin 2, a gene conserved on primate evolution. Proc. Natl. Acad. Sci. USA 2003, 100, 13013–13018.
- Malassine, A.; Dupressoir A, Marceau G, Vernochet C, Benit L, Kanellopoulos C, Sapin V, Heidmann T. 2005 Syncytin-A and syncytin-B, two fusogenic placenta- specific murine envelope genes of retroviral origin conserved in Muridae. Proc. Natl Acad. Sci. USA 102, 725 – 730.
- Handschuh, K.; Tsatsaris, V.; Gerbaud, P.; Cheynet, V.; Oriol, G.; Mallet, F.; Evain-Brion, D. Expression of herv-w env glycoprotein (syncytin) in the extravillous trophoblast of first trimester human placenta. Placenta 2005, 26, 556–562.
- Muir, A.; Lever, A.M.; Moffett, A. Human endogenous retrovirus-w envelope (syncytin) is expressed in both villous and extravillous trophoblast populations. J. Gen. Virol. 2006, 87, 2067–2071.
- Hayward, M.D.; Potgens, A.J.; Drewlo, S.; Kaufmann, P.; Rasko, J.E. Distribution of human endogenous retrovirus type w receptor in normal human villous placenta. Pathology 2007, 39, 406–412.
- Cornelis, Guillaume, et al. “Retroviral envelope gene captures and syncytin exaptation for placentation in marsupials.” Proceedings of the National Academy of Sciences (2015): 201417000.
- Heidmann O, Vernochet C, Dupressoir A, Heidmann T. 2009 Identification of an endogenous retroviral envelope gene with fusogenic activity and placenta- specific expression in the rabbit: a new “syncytin” in a third order of mammals. Retrovirology 6, 107.
- Cornelis G, Heidmann O, Bernard-Stoecklin S, Reynaud K, Veron G, Mulot B, Dupressoir A, Heidmann T. 2012 Ancestral capture of syncytin- Car1, a fusogenic endogenous retroviral envelope gene involved in placentation and conserved in Carnivora. Proc. Natl Acad. Sci. USA 109, E432 – E441.
- Lavialle, C., Cornelis, G., Dupressoir, A., Esnault, C., Heidmann, O., Vernochet, C., & Heidmann, T. (2013). Paleovirology of ‘syncytins’, retroviral env genes exapted for a role in placentation. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 368(1626), 1471-2970.
- Lokossou, Adjimon Gatien, Caroline Toudic, and Benoit Barbeau. “Implication of Human Endogenous Retrovirus Envelope Proteins in Placental Functions.” Viruses 6.11 (2014): 4609-4627.
- Vargas, Amandine, et al. “Syncytin-2 plays an important role in the fusion of human trophoblast cells.” Journal of molecular biology 392.2 (2009): 301-318.
- Lee, X., Keith Jr., J.C., Stumm, N., Moutsatsos, I., McCoy, J.M., Crum, C.P., Genest, D., Chin, D., Ehrenfels, C., Pijnenborg, R., van Assche, F.A., Mi, S., 2001. Downregulation of placental syncytin expression and abnormal protein localization in pre- eclampsia. Placenta 22, 808–812.
- Keith Jr., J.C., Pijnenborg, R., Van Assche, F.A., 2002. Placental syncytin expression in normal and preeclamptic pregnancies. Am. J. Obstet. Gynecol. 187, 1122–1123 author reply 1123–1124.
- Knerr, I., Beinder, E., Rascher, W., 2002. Syncytin, a novel human endogenous retroviral gene in human placenta: evidence for its dysregulation in preeclampsia and HELLP syndrome. Am. J. Obstet. Gynecol. 186, 210–213.
- Chen, C.P., Wang, K.G., Chen, C.Y., Yu, C., Chuang, H.C., Chen, H., 2006. Altered placental syncytin and its receptor ASCT2 expression in placental development and pre- eclampsia. BJOG 113, 152–158.
- Chen, C.P., Chen, L.F., Yang, S.R., Chen, C.Y., Ko, C.C., Chang, G.D., Chen, H., 2008. Functional characterization of the human placental fusogenic membrane protein syncytin 2. Biol. Reprod. 79, 815–823.
- Kudaka, W., Oda, T., Jinno, Y., Yoshimi, N., Aoki, Y., 2008. Cellular localization of placenta-specific human endogenous retrovirus (HERV) transcripts and their possible implication in pregnancy-induced hypertension. Placenta 29, 282–289.
- Langbein, M., Strick, R., Strissel, P.L., Vogt, N., Parsch, H., Beckmann, M.W., Schild, R.L., 2008. Impaired cytotrophoblast cell–cell fusion is associated with reduced Syncytin and increased apoptosis in patients with placental dysfunction. Mol. Reprod. Dev. 75, 175–183.
- Vargas, A., Toufaily, C., Lebellego, F., Rassart, E., Lafond, J., Barbeau, B., 2011. Reduced expression of both Syncytin 1 and Syncytin 2 correlates with severity of pre-eclampsia. Reprod. Sci. 18, 1085–1091.
- Dupressoir, Anne, et al. “Syncytin-A knockout mice demonstrate the critical role in placentation of a fusogenic, endogenous retrovirus-derived, envelope gene.” Proceedings of the National Academy of Sciences 106.29 (2009): 12127-12132.
- Dupressoir A, Vernochet C, Harper F, Guegan J, Dessen P, Pierron G, Heidmann T (2011) A pair of co-opted retroviral envelope syncytin genes is required for formation of the two-layered murine placental syncytiotrophoblast. Proc Natl Acad Sci USA 108:E1164–E1173.
- Manghera, Mamneet, Jennifer Ferguson, and Renée Douville. “Endogenous retrovirus-K and nervous system diseases.” Current neurology and neuroscience reports 14.10 (2014): 1-10.
- Raúl, Alelú-Paz, and Iturrieta-Zuazo Ignacio. “Human endogenous retroviruses: Their possible role in the molecular etiology of the schizophrenia.” Open Journal of Genetics 2012 (2012).
- Hill, Austin Bradford. “The environment and disease: association or causation?.” Proceedings of the Royal Society of Medicine 58.5 (1965): 295.
- Cegolon, Luca, et al. “Human endogenous retroviruses and cancer prevention: evidence and prospects.” BMC cancer 13.1 (2013): 4. .
- Downey, Ronan F., et al. “Human endogenous retrovirus K and cancer: innocent bystander or tumorigenic accomplice?.” International Journal of Cancer (2014).
- Kassiotis, George. “Endogenous retroviruses and the development of cancer.” The Journal of Immunology 192.4 (2014): 1343-1349.
- Salmons, Brian, James S. Lawson, and Walter H. Günzburg. “Recent developments linking retroviruses to human breast cancer: infectious agent, enemy within or both?.” Journal of General Virology 12 (2014): 2589-2593.
- Fimereli, Danai, et al. “No significant viral transcription detected in whole breast cancer transcriptomes.” BMC cancer 15.1 (2015): 147.
- Rincon, Liliana, et al. “K-type human endogenous retroviral elements in human melanoma.” Advances in Genomics & Genetics 4 (2014).
- Wallace, Tiffany A., et al. “Elevated HERV-K mRNA expression in PBMC is associated with a prostate cancer diagnosis particularly in older men and smokers.” Carcinogenesis (2014): bgu114.
- Balada, Eva, Miquel Vilardell-Tarrés, and Josep Ordi-Ros. “Implication of human endogenous retroviruses in the development of autoimmune diseases.” International reviews of immunology 29.4 (2010): 351-370.
- Fierabracci, A. “Unravelling the role of infectious agents in the pathogenesis of human autoimmunity: the hypothesis of the retroviral involvement revisited.” Current molecular medicine 9.9 (2009): 1024-1033.
- Krone, Bernd, and John M. Grange. “Paradigms in multiple sclerosis: time for a change, time for a unifying concept.” Inflammopharmacology 19.4 (2011): 187-195. .
- Antony, Joseph M., et al. “Human endogenous retroviruses and multiple sclerosis: innocent bystanders or disease determinants?.” Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 1812.2 (2011): 162-176.
- Tugnet, Nicola, et al. “Human endogenous retroviruses (HERVs) and autoimmune rheumatic disease: Is there a link?.” The open rheumatology journal 7 (2013): 13. .
- Nelson, Paul N., et al. “Rheumatoid Arthritis is Associated with IgG Antibodies to Human Endogenous Retrovirus Gag Matrix: A Potential Pathogenic Mechanism of Disease?.” The Journal of rheumatology 41.10 (2014): 1952-1960.
- Nelson, P., et al. “Viruses as potential pathogenic agents in systemic lupus erythematosus.” Lupus 23.6 (2014): 596-605. Wu, Zhouwei, et al. “DNA methylation modulates HERV-E expression in CD4+ T cells from systemic lupus erythematosus patients.” Journal of dermatological science (2015).
- Reyes, A., Haynes, M., Hanson, N., Angly, F.E., Heath, A.C., Rohwer, F., and Gordon, J.I. (2010). Viruses in the faecal microbiota of monozygotic twins and their mothers. Nature 466, 334–338.
- Minot, S., Sinha, R., Chen, J., Li, H., Keilbaugh, S.A., Wu, G.D., Lewis, J.D., and Bushman, F.D. (2011). The human gut virome: inter-individual variation and dynamic response to diet. Genome Res. 21, 1616–1625.
- Zhang T, Breitbart M, Lee WH, Run JQ, Wei CL, Soh SW, et al. RNA viral community in human feces: prevalence of plant pathogenic viruses. PLoS Biol. 2006; 4: e3.
- Lagier JC, Million M, Hugon P, Armougom F, Raoult D. Human gut microbiota: repertoire and variations. Front Cell Infect Microbiol. 2012; 2: 136).
- Witsø E, Palacios G, Cinek O, Stene LC, Grinde B, Janowitz D, et al. High prevalence of human enterovirus a infections in natural circulation of human enteroviruses. J Clin Microbiol. 2006; 44: 4095-4100.
- Breitbart M, Hewson I, Felts B, et al. Metagenomic analyses of an uncultured viral community from human feces. J Bacteriol 2003; 185:6220–3.
- Breitbart M, Haynes M, Kelley S, et al. Viral diversity and dynamics in an infant gut. Res Microbiol 2008;159:367–73.
- Smuts HE. Novel Gyroviruses, including Chicken Anaemia Virus, in Clinical and Chicken Samples from South Africa. Adv Virol. 2014; 2014: 321284.
- Finkbeiner SR, Allred AF, Tarr PI, Klein EJ, Kirkwood CD, Wang D. Metagenomic analysis of human diarrhea: viral detection and discovery. PLoS Pathog 2008;4:e1000011.
- Victoria JG, Kapoor A, Li L, et al. Metagenomic analyses of viruses in stool samples from children with acute flaccid paralysis. J Virol 2009;83:4642–51.
- Chen AC, McMillan NA, Antonsson A. Human papillomavirus type spectrum in normal skin of individuals with or without a history of frequent sun exposure. J Gen Virol. 2008; 89: 2891-2897.
- Li L, Kapoor A, Slikas B, Bamidele OS, Wang C, Shaukat S. Multiple diverse circoviruses infect farm animals and are commonly found in human and chimpanzee feces. J Virol. 2010; 84: 1674-1682.
- Foulongne V, Sauvage V, Hebert C, Dereure O, Cheval J, Gouilh MA, et al. Human skin microbiota: high diversity of DNA viruses identified on the human skin by high throughput sequencing. PLoS One. 2012; 7: e38499.
- Hino, S., and Miyata, H. (2007). Torque teno virus (TTV): current status. Rev. Med. Virol. 17, 45–57.
- Bernardin F, Operskalski E, Busch M, Delwart E. Transfusion transmission of highly prevalent commensal human viruses. Transfusion. 2010; 50: 2474- 2483.
- De Vlaminck, Iwijn, et al. “Temporal response of the human virome to immunosuppression and antiviral therapy.” Cell 155.5 (2013): 1178-1187.
- Schwarze-Zander C, Blackard JT, Rockstroh JK. Role of GB virus C in modulating HIV disease. Expert Rev Anti Infect Ther. 2012; 10: 563-572.
- Mahony JB. Detection of respiratory viruses by molecular methods. Clin Microbiol Rev. 2008; 21: 716-747.
- Schildgen O, Müller A, Allander T, Mackay IM, Völz S, Kupfer B, et al. Human bocavirus: passenger or pathogen in acute respiratory tract infections? Clin Microbiol Rev. 2008; 21: 291-304.
- Willner D, Furlan M, Haynes M, Schmieder R, Angly FE, Silva J, et al. Metagenomic analysis of respiratory tract DNA viral communities in cystic fibrosis and non-cystic fibrosis individuals. PLoS One. 2009; 4: e7370.
- Staras, Stephanie AS, et al. “Seroprevalence of cytomegalovirus infection in the United States, 1988–1994.” Clinical Infectious Diseases 43.9 (2006): 1143-1151.
- Simanek, Amanda M., et al. “Seropositivity to cytomegalovirus, inflammation, all-cause and cardiovascular disease-related mortality in the United States.” PloS one 6.2 (2011): e16103.
- Fülöp, T., Anis Larbi, and Graham Pawelec. “Human T cell aging and the impact of persistent viral infections.” Frontiers in immunology 4 (2013).
- Børglum, A. D., et al. “Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci.” Molecular psychiatry 19.3 (2014): 325-333.
- Nellåker, Christoffer, et al. “Transactivation of elements in the human endogenous retrovirus W family by viral infection.” Retrovirology 3.1 (2006): 44.
- Perron, Hervé, et al. “Molecular characteristics of Human Endogenous Retrovirus type-W in schizophrenia and bipolar disorder.” Translational psychiatry 2.12 (2012): e201. .
- Leboyer, Marion, et al. “Human endogenous retrovirus type W (HERV-W) in schizophrenia: A new avenue of research at the gene-environment interface.” The World Journal of Biological Psychiatry 14.2 (2013): 80-90.