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 Austin Bradford Hill 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).
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