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Herpes viruses cause a wide range of latent, recurring infections including oral and genital herpes, cytomegalovirus, and chicken pox.
- Recognize the attributes of herpes viruses
- Herpesviridae is a large family of DNA viruses that cause diseases in animals, including humans.
- The structure of herpes viruses consists of a relatively large double-stranded, linear DNA genome encased within an icosahedral protein cage called the capsid, which is wrapped in a lipid bilayer called the envelope.
- Notable herpes viruses include herpes simplex viruses 1 and 2, Varicella zoster virus (the causative agent of shingles and chicken pox), cytomegalovirus, and Kaposi’s sarcoma virus.
- There is no method to eradicate herpes virus from the body, but antiviral medications, such as acyclovir, can reduce the frequency, duration, and severity of outbreaks.
- tegument: A natural covering of the body or of a bodily organ.
- capsid: The outer protein shell of a virus.
- virion: A single individual particle of a virus (the viral equivalent of a cell).
Herpesviridae is a large family of DNA viruses that cause diseases in animals, including humans. The members of this family are also known as herpes viruses. The family name is derived from the Greek word herpein (“to creep”), referring to the latent, recurring infections typical of this group of viruses.
Animal herpes viruses all share some common properties. The structure of these viruses consists of a relatively large double-stranded, linear DNA genome encased within an icosahedral protein cage called the capsid, which is wrapped in a lipid bilayer called the envelope. The envelope is joined to the capsid by means of a tegument. This complete particle is known as the virion. HSV-1 and HSV-2 each contain at least 74 genes within their genomes, although speculation over gene crowding allows as many as 84 unique protein-coding genes by 94 putative pen reading frames. These genes encode a variety of proteins involved in forming the capsid, tegument and envelope of the virus, as well as controlling the replication and infectivity of the virus.
Types of herpes viruses
There are nine distinct herpes viruses which cause disease in humans:
- HHV‑1 Herpes simplex virus-1 (HSV-1)
- HHV-2 Herpes simplex virus-2 (HSV-2)
- HHV-3 Varicella zoster virus (VZV)
- HHV-4 Epstein-Barr virus (EBV)
- HHV-5 Cytomegalovirus (CMV)
- HHV-6A/B Roseolovirus, Herpes lymphotropic virus
- HHV-7 Pityriasis Rosea
- HHV-8 Kaposi’s sarcoma-associated herpesvirus
Of particular interest include HSV-1 and HSV-2, which cause oral and/or genital herpes, HSV-3 which causes chickenpox and shingles, and HHV-5 which causes mononucleosis-like symptoms, and HHV-8 which causes a Kaposi’s sarcoma, a cancer of the lymphatic epithelium.
Infection is caused through close contact with an infected individual. Infection is initiated when a viral particle comes in contact with the target cell specific to the individual herpes virus. Viral glycoproteins bind cell surface receptors molecules on the cell surface, followed by virion internalization and disassembly. Viral DNA then migrates to the cell nucleus where replication of viral DNA and transcription of viral genes occurs.
During symptomatic infection, infected cells transcribe lytic viral genes. In some host cells, a small number of viral genes termed latency-associated transcripts accumulate instead. In this fashion, the virus can persist in the cell (and thus the host) indefinitely. While primary infection is often accompanied by a self-limited period of clinical illness, long-term latency is symptom-free.
Reactivation of latent viruses
This has been implicated in a number of diseases (e.g. Shingles, Pityriasis Rosea). Following activation, transcription of viral genes transitions from latency-associated transcripts to multiple lytic genes; these lead to enhanced replication and virus production. Often, lytic activation leads to cell death. Clinically, lytic activation is often accompanied by emergence of non-specific symptoms such as low grade fever, headache, sore throat, malaise, and rash, as well as clinical signs such as swollen or tender lymph nodes, and immunological findings such as reduced levels of natural killer cells.
There is no method to eradicate the herpes virus from the body, but antiviral medications, such as acyclovir, can reduce the frequency, duration, and severity of outbreaks. Analgesics such as ibuprofen and acetaminophen can reduce pain and fever. Topical anesthetic treatments such as prilocaine, lidocaine, benzocaine or tetracaine can also relieve itching and pain.
Citation: Kobiler O, Weitzman MD (2019) Herpes simplex virus replication compartments: From naked release to recombining together. PLoS Pathog 15(6): e1007714. https://doi.org/10.1371/journal.ppat.1007714
Editor: Katherine R. Spindler, University of Michigan Medical School, UNITED STATES
Published: June 3, 2019
Copyright: © 2019 Kobiler, Weitzman. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: Studies of HSV replication in the Kobiler lab are supported by funds to OK from the Israel Science foundation (ISF 1387/14), an EU CIG grant (FP7-2012-333653), and a Marguerite Stolz Research Fellowship. Research on HSV replication compartments is supported in the Weitzman lab by grants to MDW from the National Institutes of Health (NS082240 and AI115104) and funds from the Children’s Hospital of Philadelphia. Work between the two labs is supported by the United States-Israel Binational Science Foundation (BSF 2015395). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
During 1986, Syed Zaki Salahuddin, Dharam Ablashi, and Robert Gallo cultivated peripheral blood mononuclear cells from patients with AIDS and lymphoproliferative illnesses. Short-lived, large, refractile cells that frequently contained intranuclear and/or intracytoplasmic inclusion bodies were documented. Electron microscopy revealed a novel virus that they named Human B-Lymphotrophic Virus (HBLV).  
Shortly after its discovery, Ablashi et al. described five cell lines that can be infected by the newly discovered HBLV. They published that HSB-2, a particular T-cell line, is highly susceptible to infection. Ablashi's pioneering research concluded by suggesting that the virus name be changed from HBLV to HHV-6, in accord with the published provisional classification of herpes viruses.  
Years later, HHV-6 was divided into subtypes. Early research (1992) described two very similar, yet unique variants: HHV-6A and HHV-6B. The distinction was warranted due to unique restriction endonuclease cleavages, monoclonal antibody reactions,  and growth patterns. 
HHV-6A includes several adult-derived strains and its disease spectrum is not well defined, although it is thought by some to be more neurovirulent.   HHV-6B is commonly detected in children with roseola infantum, as it is the etiologic agent for this condition. Within these two viruses is a sequence homology of 95%. 
In 2012, HHV-6A and HHV-6B were officially recognized as distinct species. 
HHV-6A and HHV-6B were recognized by the International Committee on Taxonomy of Viruses (ICTV) as distinct species in 2012. Human Roseoloviruses include HHV-6A, HHV-6B and HHV-7. 
Herpesvirus was established as a genus in 1971 in the first report of the ICTV. This genus consisted of 23 viruses among 4 groups.  In 1976, a second ICTV report was released in which this genus was elevated to the family level — the herpetoviridae. Because of possible confusion with viruses derived from reptiles, the family name was changed in the third report (1979) to herpesviridae. In this report, the family Herpesviridae was divided into 3 subfamilies (alphaherpesvirinae, betaherpesvirinae and gammaherpesvirinae) and 5 unnamed genera 21 viruses were recognized as members of the family. 
In 2009, the order Herpesvirales was created. This was necessitated by the discovery that the herpes viruses of fish and molluscs are only distantly related to those of birds and mammals. Order Herpesvirales contains three families, the Herpesviridae, which contains the long-recognized herpesviruses of mammals, birds, and reptiles, plus two new families — the family Alloherpesviridae which incorporates herpes viruses of bony fish and frogs, and the family Malacoherpesviridae which contains viruses of molluscs. 
As of 2012, this order currently has 3 families, 4 subfamilies (1 unassigned), 18 genera (4 unassigned) and 97 species. 
The diameter of an HHV-6 virion is about 2000 angstroms.  The virion's outer portion consists of a lipid bilayer membrane that contains viral glycoproteins and is derived from that of the host. Below this membrane envelope is a tegument which surrounds an icosahedral capsid, composed of 162 capsomeres. The protective capsid of HHV-6 contains double stranded linear DNA.
During maturation of HHV-6 virions, human cell membranes are used to form viral lipid envelopes (as is characteristic of all enveloped viruses). During this process HHV-6 utilizes lipid rafts, which are membranous microdomains enriched by cholesterol, sphingolipids, and glycosylphosphatidylinositol-anchored proteins.  Early researchers suspected that HHV-6 virions mature in the nucleus some even incorrectly published this, as they generalized and applied to HHV-6 what was known about other viruses. However, researched published in 2009 suggests that the HHV-6 virus utilizes trans-Golgi-network-derived vesicles for assembly. 
The genetic material of HHV-6 is composed of linear (circular during an active infection), double stranded DNA which contains an origin of replication, two 8–10 kb left and right direct repeat termini, and a unique segment that is 143–145kb. 
The origin of replication (often labeled as "oriLyt" in the literature) is where DNA replication begins.  The direct repeat termini (DRL and DRR) possess a repeated TTAGGG sequence, identical to that of human telomeres. Variability in the number of telomeric repeats is observed in the range of 15–180.   These termini also contain pac-1 and pac-2 cleavage and packing signals that are conserved among herpesviruses.
The unique segment contains seven major core gene blocks (U27–U37, U38–U40, U41–U46, U48–U53, U56–U57, U66EX2–U77, and U81–U82),  which is also characteristic of herpesviruses. These conserved genes code for proteins that are involved in replication, cleavage, and packing of the viral genome into a mature virion.  Additionally, they code for a number of immunomodulatory proteins. The unique segment also possesses a block of genes (U2–U19) that are conserved among HHV-6, HHV-7, and Cytomegaloviruses (the betaherpesviruses). A number of the unique segment genes are associated with, for instance, the HCMV US22 family (InterPro: IPR003360). The table below outlines some of their known properties. 
|IE-A (IE1? U89?)||Immediate early||Part of IE locus  — impairs interferon gene expression to restrict the development of cellular anti-viral measures, favoring a successful infection — not in membrane — activates viral DNA polymerases, involved in rolling circle replication — expression of this gene may be modulated by micro RNAs |
|IE-B||Immediate early||Part of IE locus  Activates viral DNA polymerases, involved in rolling circle replication|
|DR1||HCMV US22 gene family|
|DR6||HCMV US22 gene family, transactivator, oncogene|
|DR7/U1||SR domain, malignant transforming activity, binds to p53|
|U2||HCMV US22 gene family — tegument protein|
|U3||HCMV UL24 homolog, HCMV US22 gene family, tegument protein — transactivating activity |
|U4||HCMV Maribavir resistance|
|U7||HCMV US22 gene family|
|U11||Strongly immunoreactive virion protein  — antigenic tegument protein|
|U12||Chemokine G protein-coupled receptor|
|U13||CMV: Represses US3 transcription|
|U14||Binds and incorporates p53 into viral particles — HCMV UL25 gene family — antigenic tegument protein|
|U15||HCMV UL25 gene family|
|U17||HCMV UL25 gene family — tegument protein|
|U20||Glycoprotein (specific to Roseolovirus) predicted immunoglobulin structure|
|U21||Binds to MHC-1 molecules and prevents antigen presenting cells from presenting HHV-6 peptides — glycoprotein, downregulates HLA I (specific to Roseolovirus)|
|U22||Late gene||Glycoprotein (absent from HHV-7, specific to Roseolovirus)|
|U23||Glycoprotein (specific to Roseolovirus)|
|U24||Inhibits proper T cell activation, reducing secretion of cytokines at infection site — phosphorylation target for kinases — glycoprotein M (gM) (specific to Roseolovirus)|
|U25||HCMV UL22 gene family, tegument protein|
|U26||Putative multiple transmembrane protein|
|U27||DNA polymerase processivity factory|
|U28||Ribonucleotide reductase large subunit, tegument protein|
|U29||Capsid assembly and DNA maturation|
|U31||Large tegument protein|
|U32||Capsid protein, hexon tips|
|U34||Membrane-associated phosphoprotein, primary envelopment|
|U35||Terminase component, DNA packaging|
|U37||Tegument protein, primary envelopment, phosphoprotein|
|U39 (gB, gp116)||Glycoprotein|
|U40||Transport, capsid assembly|
|U41||Early gene||Major DNA binding protein|
|U42||Tegument protein, cell cycle block, transactivator|
|U43||DNA Helicase-primase complex|
|U46||Glycoprotein N, membrane protein|
|U47 (gO, O)||Glycoprotein O, associates with lipid rafts, exists in two forms, gO-120K and gO-80K, and gO-80K contains complex type N-linked oligosaccharides which are incorporated into viral particles|
|U48 (gH, gp100)||Glycoprotein gH, virion constituent, part of CD46 gQ1/gQ2/gL/gH ligand complex, associates with lipid rafts|
|U49||Virion-associated regulatory protein, fusion protein|
|U51||Early gene||G protein-coupled chemokine receptor, preventing expression greatly reduces replication — increases intracellular levels of second messenger inositol phosphate, promotes chemotaxis – early gene, along with U41 and U69 |
|U53||Protease,  capsid assembly protein|
|U54||Tegument protein, virion transactivator|
|U55||Role in RNA synthesis, dUTPase|
|U57||Major capsid protein|
|U64||DNA packaging: tegument protein|
|U69||Early gene||Tegument protein kinase (Ganciclovir kinase) involved in replication |
|U71||Myristylated virion protein|
|U72 (gM)||Glycoprotein M|
|U74||DNa helicase-primase complex|
|U76||DNA packaging, virion protein|
|U80||Predicted immunoglobulin structure|
|U82 (gL, gp80)||Glycoprotein L, virion constituent, part of CD46 gQ1/gQ2/gL/gH ligand complex, associates with lipid rafts|
|U83||Secreted chemotactic (chemoattractant) glycoprotein, binds to chemokine receptors, recruits host cells that secrete chemokines specific to U51|
|U85||Glycoprotein (specific to Roseolovirus)|
|U90||IE-A (IE 1)||Transactivator|
|U94||Latency (immediate early or early gene)||Involved in transcriptional repression of lytic genes – aids in the specific integration of HHV-6A/HHV-6B into the telomeres — highly expressed during latency — parvovirus rep homolog (absent in HHV-7)|
|U95||CMV US22 gene family – colocalizes and interacts with the mitochondrial GRIM-19 protein, an essential component of the oxidative phosphorylation system  — binds to nuclear factor-kappa B (NF-κB), deregulation of which has been postulated to contribute to cancer |
|U100 (Gp82-105)||Late gene||Glycoprotein Q, virion constituent, associates with lipid rafts|
|gQ1||Glycoprotein, complexes with gH and gL to form viral ligand to CD46 receptor – modified by N-glycosylation — expressed in two different forms: an 80-kDa form (gQ1-80K) and a 74-kDa form (gQ1-74K) – only gQ1-80K, but not gQ1-74K, forms the CD46 ligand complex with gQ2, gH, and gL  Associates with lipid rafts.|
|gM1||Lipid-raft-specific ganglioside, incorporated into virion|
|gQ2||Glycoprotein, forms gH/gL/gQ1/gQ2 complex, part of receptor ligand – essential for viral growth, associates with lipid rafts — exists in two forms: gQ2-34K and gQ2-37K|
|Micro RNAs||hhv6b-miR-Ro6-1, -Ro6-2, -Ro6-3, and -Ro6-4. May regulate early transcription|
|P100 aka p101||Immunogenic, constituent of tegument|
|ORF-1 (DR7)||Binds and inhibits transcriptional activity of p53 – can transform human epidermal keratinocytes and NIH 3T3 cells in vitro – cells expressing ORF-1 protein produce fibrosarcomas when injected into nude mice|
HHV-6 receptor Edit
When an extracellular HHV-6 virion comes across human cells, it encounters the human receptor protein cluster of differentiation 46 (CD46), which plays a role in regulating the complement system. The CD46 protein possesses a single variable region, as a result of alternative splicing. As such, at least fourteen isoforms of CD46 exist, all of which bind HHV-6a. 
The extracellular region of CD46 contains four short consensus repeats of about 60 amino acids that fold into a compact beta-barrel domain surrounded by flexible loops.  As has been demonstrated for CD46 with other ligands, the CD46 protein structure linearizes upon binding HHV-6. While their precise interaction has not yet been determined, the second and third SCR domains have been demonstrated as required for HHV-6 receptor binding and cellular entry.
HHV-6 receptor ligand Edit
Mori et al. first identified the gene product gQ1, a glycoprotein unique to HHV-6, and found that it forms a complex with gH and gL glycoproteins.   They believed that this heterotrimer complex served as the viral ligand for CD46.  Soon thereafter, another glycoprotein named gQ2 was identified and found to be part of the gH/gL/gQ1 ligand complex, forming a heterotetramer that was positively identified as the viral CD46 ligand.  The exact process of entry is not yet well understood.
Salivary glands Edit
The salivary glands have been described as an in vivo reservoir for HHV-6 infection. 
Researchers  conducted a study to show that T cells are highly infectable by HHV-6.
Nervous system Edit
During the year 2011, researchers at the National Institutes of Health attempted to elucidate the then unknown method whereby HHV-6a gains entry into the nervous system. As such, they autopsied the brains of around 150 subjects. When various anatomical regions were assayed for their viral load, olfactory tissues were found to have the highest HHV-6 content. They concluded that these tissues are the entry point for HHV-6a. 
The results above are consistent with those of previous studies that involved HSV-1 (and a number of other viruses), which also disseminates into the CNS through olfactory tissue. 
Researchers also hypothesized that olfactory ensheathing cells (OECs), a group of specialized glial cells found in the nasal cavity, may have a role in HHV-6 infectivity.  They suspected this association as a result of OECs having properties similar to those of astrocytes, another type of glial cell that was previously identified as being susceptible to HHV-6 infection.  Research continued by infecting OECs in vitro with both types of HHV-6. Ultimately, only OECs in which HHV-6a was used tested positive for signs of de novo viral synthesis, as is also characteristic of astrocytes. 
Once inside, two outcomes have been described: active and inactive infections.
Active infection Edit
Active infections involve the linear dsDNA genome circularizing by end to end covalent linkages. This process was first reported for the herpes simplex virus.  Once circularized, HHV-6 begins to express what are known as "immediate early" genes. These gene products are believed to be transcription activators  and may be regulated by the expression of viral micro RNAs.  Subsequent expression of "early genes" then occurs and activates, for instance, viral DNA polymerases. Early genes are also involved in the rolling circle replication that follows. 
HHV-6's replication results in the formation of concatemers, which are long molecules that contain several repeats of a DNA sequence.  These long concatemers are then cleaved between the pac-1 and pac-2 regions by ribozymes for packaging of the genome into individual virions. 
Inactive infection Edit
Not all newly infected cells begin rolling circle replication. Herpesviruses may enter a latent stage, inactively infecting their human host. Since its discovery in 1993, this phenomenon has been found among all of the betaherpesviruses. 
Other betaherpesviruses establish latency as a nuclear episome, which is a circular DNA molecule (analogous to plasmids). For HHV-6, latency is believed to occur exclusively through the integration of viral telomeric repeats into human subtelomeric regions.  Only one other virus, Marek's disease virus, is known to achieve latency in this fashion.  This phenomenon is possible as a result of the telomeric repeats found within the direct repeat termini of HHV-6's genome.
The right direct repeat terminus integrates within 5 to 41 human telomere repeats, and preferentially does so into the proximal end  of chromosomes 9, 17, 18, 19, and 22, but has also occasionally been found in chromosomes 10 and 11.  Nearly 70 million individuals are suspected to carry chromosomally integrated HHV-6.  
A number of genes expressed by HHV-6 are unique to its inactive latency stage. These genes involve maintaining the genome and avoiding destruction of the host cell.  For instance, the U94 protein is believed to repress genes that are involved in cellular lysis (apoptosis) and also may aid in telomeric integration.  Once stored in human telomeres, the virus is reactivated intermittently. 
The specific triggers for reactivation are not well understood. Some researchers have suggested that injury, physical or emotional stress, and hormonal imbalances could be involved. 
Researchers during 2011 discovered that reactivation can positively be triggered in vitro by histone deacetylase inhibitors. Once reactivation begins, the rolling circle process is initiated and concatemers are formed as described above. 
Human herpesvirus 6 lives primarily on humans and, while variants of the virus can cause mild to fatal illnesses, can live commensally on its host.  It has been demonstrated that HHV-6 fosters the progression of HIV-1 upon coinfection in T cells.  HHV-6 upregulates the expression of the primary HIV receptor CD4, thus expanding the range of HIV susceptible cells. Several studies also have shown that HHV-6 infection increases production of inflammatory cytokines that enhance in vitro expression of HIV-1, such as TNF-alpha,  IL-1 beta, and IL-8.  A more recent in vivo study shows HHV-6A coinfection to dramatically accelerate the progression from HIV to AIDS in pigtailed macaques. 
HHV-6 has also been demonstrated to transactivate Epstein–Barr virus. 
Humans acquire the virus at an early age, some as early as less than one month of age. HHV-6 primary infections account for up to 20% of infant emergency room visits for fever in the United States   and are associated with several more severe complications, such as encephalitis, lymphadenopathy, myocarditis and myelosuppression. The prevalence of the virus in the body increases with age (rates of infection are highest among infant between 6 and 12 months old) and it is hypothesized that this is due to the loss of maternal antibodies in a child that protect him or her from infections. 
There are inconsistencies with the correlations between age and seropositivity: According to some reports there is a decrease of seropositivity with the increase of age, while some indicate no significant decline, and others report an increased rate of seropositivity for individuals age 62 and older. After primary infection, latency is established in salivary glands, hematopoietic stem cells, and other cells, and exists for the lifetime of the host.
Geographical distribution Edit
The virus is known to be widespread around the world. An HHV-6 infection rate of 64–83% by age 13 months has been reported for countries including the United States, United Kingdom, Japan and Taiwan.   Studies have found seroprevalence varying "from approximately 39 to 80% among ethnically diverse adult populations from Tanzania, Malaysia, Thailand, and Brazil."  There are no significant differences among ethnic groups living in the same geographical location or between sexes. While HHV-6B is present in almost all of the world's populations, HHV-6A appears to be less frequent in Japan, North America, and Europe. 
Transmission is believed to occur most frequently through the shedding of viral particles into saliva. Both HHV-6B and HHV-7 are found in human saliva, the former being at a lower frequency. Studies report varying rates of prevalence of HHV-6 in saliva (between 3–90%),  and have also described the salivary glands as an in vivo reservoir for HHV-6. The virus infects the salivary glands, establishes latency, and periodically reactivates to spread infection to other hosts. 
Vertical transmission has also been described, and occurs in approximately 1% of births in the United States.   This form is easily identifiable as the viral genome is contained within every cell of an infected individual.
The diagnosis of HHV-6 infection is performed by both serologic and direct methods. The most prominent technique is the quantification of viral DNA in blood, other body fluids, and organs by means of real-time PCR. 
The classical presentation of primary HHV-6b infection is as exanthema subitum (ES) or "roseola", featuring a high temperature followed by a rash. However, one study (1997) indicated that a rash is not a distinguishing feature of HHV-6 infection, with rates similar to non-HHV-6 infections (10–20% of febrile children in both groups). HHV-6 infections more frequently present with high temperatures (over 40C), at a rate of around two thirds compared to less than half in the non-HHV-6 patients. Similarly significant differences were seen in malaise, irritability, and tympanic membrane inflammation. 
Primary infection in adults tend to be more severe. 
Diagnosis for the virus, particularly HHV-6B, is vital for the patient because of the infection's adverse effects. Symptoms that point to this infection, such as rashes, go unnoticed in patients that receive antibiotics because they can be misinterpreted as a side-effect of the medicine.  HHV-6B is known to be associated with the childhood disease roseola infantum, as well as other illnesses caused by the infection. These include hepatitis, febrile convulsions, and encephalitis. Children who suffer from exanthema subitum, caused by an HHV-6B infection, experience fevers lasting 3 to 5 days rashes on the torso, neck, and face and sometimes febrile convulsions, however, the symptoms are not always present together. Primary infections in adults are rare since most occurrences are in children. When the infection does occur for the first time in an adult the symptoms can be severe.
The virus periodically re-activates from its latent state, with HHV-6 DNA being detectable in 20–25% of healthy adults in the United States. In the immunocompetent setting, these re-activations are often asymptomatic, but in immunosuppressed individuals there can be serious complications. HHV-6 re-activation causes severe disease in transplant recipients and can lead to graft rejection, often in consort with other betaherpesviridae. Likewise in HIV/AIDS, HHV-6 re-activations cause disseminated infections leading to end organ disease and death. Although up to 100% of the population are exposed (seropositive) to HHV-6, most by 3 years of age, there are rare cases of primary infections in adults. In the United States, these have been linked more with HHV-6a, which is thought to be more pathogenic and more neurotropic and has been linked to several central nervous system-related disorders.
HHV-6 has been reported in multiple sclerosis patients  and has been implicated as a co-factor in several other diseases, including chronic fatigue syndrome,  fibromyalgia, AIDS,  optic neuritis, cancer, and temporal lobe epilepsy. 
Multiple sclerosis Edit
Multiple sclerosis (MS) is an autoimmune and inflammatory disorder of the nervous system that results in demyelination of axons in the brain and spinal cord. The history of MS in the context of HHV-6 began during 1995 when Peter Challoner, a scientist at PathoGenesis Corporation of Seattle, began looking for non-human genetic sequences in the brains of MS patients. He found an unusually high expression of HHV-6 DNA within oligodendrocytes. He also noticed a higher concentration of infected cells in areas where demyelination had occurred.  His research was likely the first published study to suggest a link between HHV-6 and MS.
Epidemiological data Edit
MS prevalence increases in populations as they are farther from the Equator.   Incidence is three times higher in those born 42 degrees latitude north and above than in those born 37 degrees north and below. Individuals are also less likely to present with MS as an adult if their childhood was spent in a low incidence region. The possibility of a causative infectious agent in association with MS has been evaluated through the lens of these epidemiological findings.
To explain the data above, two hypotheses were proposed.  The first is known as the Poliomyelitis hypothesis and suggests that infection at a young age confers immunity but adult infection increases MS risk. The second is known as the Prevalence hypothesis, and suggests that MS is caused by a pathogen that is more common in regions with high rates of MS. This pathogen would be widespread and cause an asymptomatic (latent) infection in most individuals. Only rarely and years after the primary infection does this hypothetical agent cause the neurological symptoms of MS. A third hypothesis essentially combines these two and also suggests the involvement of multiple pathogens. The third may best apply to the epidemiological data.  
Possible viral involvement Edit
The Epstein–Barr virus (EBV) paradox is also noteworthy, as HHV-6 has been reported to transactivate EBV.  Individuals are at a 10-fold less risk of MS if they are seronegative for EBV. However, among individuals who are positive, those that acquire EBV infection later in life are at a 3-fold greater risk for MS.
Research suggests that viral infections can be tied even closer to MS. EBV antibodies in healthy individuals remain constant, whereas antibody levels in individuals who later develop MS begin to increase and plateau between 20 and 30 years of age, regardless of age of onset.
More specific to HHV-6, researchers in 2004 discovered that the initial stages of MS are associated with high levels of the active virus.  Soon thereafter, researchers discovered that levels of active HHV-6 are also elevated during relapses/exacerbations of MS. 
Researchers have demonstrated that levels of HHV-6 IgG1 and IgM antibodies are elevated in MS patients relative to controls.  In fact, research published in 2014 found that increases in anti-HHV-6A/B IgG and IgM titers are predictive of MS relapse. 
Analysis of the epidemiological, serological, and immunological data above supports the association between an infectious agent and MS. However, the exact mechanism of a possible viral influence on the manifestation of MS is less clear. Although, a few mechanisms have been suggested: molecular mimicry, phosphorylation pathways, and cytokines.     
Molecular mimicry Edit
The first study to specifically investigate HHV-6-related demyelination appeared in the literature during 1996, when a previously healthy 19-month-old child developed acute encephalopathy. Levels of myelin basic protein were elevated in his cerebrospinal fluid, suggesting that demyelination was occurring.  This link was almost forgotten, until four years later when an MS-related study was published showing an HHV-6 prevalence of 90% among demyelinated brain tissues. In comparison, a mere 13% of disease-free brain tissues possessed the virus. 
The molecular mimicry hypothesis, in which T cells are essentially confusing an HHV-6 viral protein with myelin basic protein, first appeared around this time. Early on in the development of this hypothesis (2002), Italian researchers used the HHV-6a variant along with bovine myelin basic protein to generate cross-reactive T cell lines. These were compared to the T cells of individuals with MS as well as those of controls, and no significant difference was found between the two. Their early research suggested that molecular mimicry may not be a mechanism that is involved in MS. 
A few months later, researchers in the United States created a synthetic peptide with a sequence identical to that of an HHV-6 peptide. They were able to show that T cells were activated by this peptide. These activated T cells also recognized and initiated an immune response against a synthetically created peptide sequence that is identical to part of human myelin basic protein. During their research, they found that the levels of these cross-reactive T cells are significantly elevated in MS patients.  Their research concluded by suggesting that HHV-6 may indeed be a causative agent for MS.
Several similar studies followed. A study from October 2014 supported the role of long-term HHV-6 infection with demyelination in progressive neurological diseases. 
Phosphorylation pathways Edit
Myelin basic protein (MBP) regularly exchanges phosphate groups with the environment, and its ability to do so has implications for proper myelin sheath integrity. More specifically, two threonine residues on MBP have been identified as the phosphorylation targets of glycogen synthase kinase and mitogen-activated protein kinase. Their action on MBP is said to aid in its ability to polymerize and bundle myelin. Phosphorylated MBP is also more resistant to several proteases. 
Among individuals with MS, these target threonines have been found to be phosphorylated less often. In fact, HHV-6 produces a transmembrane protein, known as U24, that is also a phosphorylation target of the kinases mentioned previously. Our kinases act on an HHV-6 protein due to a shared sequence of seven amino acids (MBP92–104=IVTPRTPPPSQGK U241–13=MDPPRTPPPSYSE). As a result, essential post-translational modifications may not be occurring for MBPs in individuals with active HHV-6 infections. 
HHV-6 has been shown to infect olfactory ensheathing cells (OECs). OECs have been investigated thoroughly in relation to spinal cord injuries, amyotrophic lateral sclerosis, and other neurodegenerative diseases. Researchers suggest that these cells possess a unique ability to remyelinate injured neurons. 
Some of the genes expressed by HHV-6 manipulate host levels of various cytokines (see section on gene products). For instance, infected cells have increased levels of interleukin-8, which is believed to induce MMP-9 repression. Elevated levels of MMP-9 have been found among individuals with MS. 
HHV-6 reactivation has also been implicated in the exacerbation of MS via a shift in Th lymphocyte subsets. 
Chronic fatigue syndrome Edit
Chronic fatigue syndrome (CFS) is a debilitating illness,  cause of which is unknown. Patients with CFS have abnormal neurological, immunological, and metabolic findings.
For many, but not all, patients who meet criteria for CFS, the illness begins with an acute, infectious-like syndrome. Cases of CFS can follow well-documented infections with several infectious agents.  A study of 259 patients with a "CFS-like" illness published shortly after HHV-6 was discovered used primary lymphocyte cultures to identify people with active replication of HHV-6. Such active replication was found in 70% of the patients vs. 20% of the control subjects ( P < 10 − 8
Subsequent studies employing only serological techniques that do not distinguish active from latent infection have produced mixed results: most, but not all, have found an association between CFS and HHV-6 infection.   
Other studies have employed assays that can detect active infection: primary cell culture, PCR of serum or plasma, or IgM early antigen antibody assays. The majority of these studies have shown an association between CFS and active HHV-6 infection,       although a few have not.  
In summary, active infection with HHV-6 is present in a substantial fraction of patients with CFS. Moreover, HHV-6 is known to infect cells of the nervous system and immune system, organ systems with demonstrable abnormalities in CFS. Despite this association, it remains unproven that reactivated HHV-6 infection is a cause of CFS.
Hashimoto's thyroiditis Edit
Hashimoto's thyroiditis is the most common thyroid disease and is characterized by abundant lymphocyte infiltrate and thyroid impairment. Recent research suggests a potential role for HHV-6 (possibly variant A) in the development or triggering of Hashimoto's thyroiditis. 
The role of HHV-6 during pregnancy leading to inflammation in the amniotic cavity has been studied. 
HHV-6A DNA was found in the endometrium of almost half of a group of infertile women, but in none of the fertile control group. Natural killer cells specific for HHV-6A, and high uterine levels of certain cytokines, were also found in the endometrium of the infertile women positive for HHV-6A. The authors suggest that HHV-6A may prove to be an important factor in female infertility. 
Many human oncogenic viruses have been identified. For instance, HHV-8 is linked to Kaposi's sarcoma,  the Epstein–Barr virus to Burkitt's lymphoma, and HPV to cervical cancer. In fact, the World Health Organization estimated (2002) that 17.8% of human cancers were caused by infection.  The typical methods whereby viruses initiate oncogenesis involve suppressing the host's immune system, causing inflammation, or altering genes.
HHV-6 has been detected in lymphomas, leukemias, cervical cancers, and brain tumors.  Various medulloblastoma cell lines as well as the cells of other brain tumors have been demonstrated to express the CD46 receptor. Viral DNA has also been identified in many other non-pathological brain tissues, but the levels are lower. 
The human P53 protein functions as a tumor suppressor. Individuals who do not properly produce this protein experience a higher incidence of cancer, a phenomenon known as Li-Fraumeni syndrome. One of HHV-6's gene products, the U14 protein, binds P53 and incorporates it into virions. Another gene product, the ORF-1 protein, can also bind and inactivate P53. Cells expressing the ORF-1 gene have even been shown to produce fibrosarcomas when injected into mice. 
Another product of HHV-6, the immediate early protein U95, has been shown to bind nuclear factor-kappa B. Deregulation of this factor is associated with cancer. 
Optic neuritis Edit
HHV-6 induced ocular inflammation has been reported three times. All three were reported in elderly individuals, two during 2007 and one during 2011. The first two were reported in Japan and France, the most recent one in Japan.   
These were believed to have occurred as a result of a reactivation, as anti-HHV-6 IgM antibody levels were low. 
Temporal lobe epilepsy Edit
Epilepsy of the mesial temporal lobe is associated with HHV-6 infection. Within this region of the brain exists three structures: the amygdala, hippocampus, and parahippocampal gyrus. Mesial temporal lobe epilepsy (MTLE) is the most common form of chronic epilepsy and its underlying mechanism is not fully understood. 
Researchers consistently report having found HHV-6 DNA in tissues that were removed from patients with MTLE. Studies have demonstrated a tendency for HHV-6 to aggregate in the temporal lobe,  with the highest concentrations in astrocytes of the hippocampus. 
However, one group of researchers ultimately concluded that HHV-6 may not be involved in MTLE related to Mesial Temporal Sclerosis. 
Liver failure Edit
The virus is a common cause of liver dysfunction and acute liver failure, and has recently been linked to periportal confluent necrosis. Furthermore, HHV-6 DNA is often detectable only in the biopsy tissues as DNA levels fall below the level of detection in blood in persistent cases. 
There are no pharmaceuticals approved specifically for treating HHV-6 infection, although the usage of Cytomegalovirus treatments (valganciclovir, ganciclovir,  cidofovir, and foscarnet) have shown some success.  These drugs are given with the intent of inhibiting proper DNA polymerization by competing with deoxy triphosphate nucleotides  or specifically inactivating viral DNA polymerases. 
Finding a treatment can be difficult when HHV-6 reactivation occurs following transplant surgery because transplant medications include immunosuppressants. 
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APOBECs and Herpesviruses
The APOBEC family of DNA cytosine deaminases provides a broad and overlapping defense against viral infections. Successful viral pathogens, by definition, have evolved strategies to escape restriction by the APOBEC enzymes of their hosts. HIV-1 and related retroviruses are thought to be the predominant natural substrates of APOBEC enzymes due to obligate single-stranded DNA replication intermediates, abundant evidence for cDNA strand C-to-U editing (genomic strand G-to-A hypermutation), and a potent APOBEC degradation mechanism. In contrast, much lower mutation rates are observed in double-stranded DNA herpesviruses and the evidence for APOBEC mutation has been less compelling. However, recent work has revealed that Epstein-Barr virus (EBV), Kaposi's sarcoma herpesvirus (KSHV), and herpes simplex virus-1 (HSV-1) are potential substrates for cellular APOBEC enzymes. To prevent APOBEC-mediated restriction these viruses have repurposed their ribonucleotide reductase (RNR) large subunits to directly bind, inhibit, and relocalize at least two distinct APOBEC enzymes - APOBEC3B and APOBEC3A. The importance of this interaction is evidenced by genetic inactivation of the EBV RNR (BORF2), which results in lower viral infectivity and higher levels of C/G-to-T/A hypermutation. This RNR-mediated mechanism therefore likely functions to protect lytic phase viral DNA replication intermediates from APOBEC-catalyzed DNA C-to-U deamination. The RNR-APOBEC interaction defines a new host-pathogen conflict that the virus must win in real-time for transmission and pathogenesis. However, partial losses over evolutionary time may also benefit the virus by providing mutational fuel for adaptation.
Keywords: APOBEC DNA cytosine deamination DNA editing evolution herpesvirus innate antiviral immunity mutation restriction factors ribonucleotide reductase.
The Double-Stranded DNA Virosphere as a Modular Hierarchical Network of Gene Sharing
Virus genomes are prone to extensive gene loss, gain, and exchange and share no universal genes. Therefore, in a broad-scale study of virus evolution, gene and genome network analyses can complement traditional phylogenetics. We performed an exhaustive comparative analysis of the genomes of double-stranded DNA (dsDNA) viruses by using the bipartite network approach and found a robust hierarchical modularity in the dsDNA virosphere. Bipartite networks consist of two classes of nodes, with nodes in one class, in this case genomes, being connected via nodes of the second class, in this case genes. Such a network can be partitioned into modules that combine nodes from both classes. The bipartite network of dsDNA viruses includes 19 modules that form 5 major and 3 minor supermodules. Of these modules, 11 include tailed bacteriophages, reflecting the diversity of this largest group of viruses. The module analysis quantitatively validates and refines previously proposed nontrivial evolutionary relationships. An expansive supermodule combines the large and giant viruses of the putative order "Megavirales" with diverse moderate-sized viruses and related mobile elements. All viruses in this supermodule share a distinct morphogenetic tool kit with a double jelly roll major capsid protein. Herpesviruses and tailed bacteriophages comprise another supermodule, held together by a distinct set of morphogenetic proteins centered on the HK97-like major capsid protein. Together, these two supermodules cover the great majority of currently known dsDNA viruses. We formally identify a set of 14 viral hallmark genes that comprise the hubs of the network and account for most of the intermodule connections.
Importance: Viruses and related mobile genetic elements are the dominant biological entities on earth, but their evolution is not sufficiently understood and their classification is not adequately developed. The key reason is the characteristic high rate of virus evolution that involves not only sequence change but also extensive gene loss, gain, and exchange. Therefore, in the study of virus evolution on a large scale, traditional phylogenetic approaches have limited applicability and have to be complemented by gene and genome network analyses. We applied state-of-the art methods of such analysis to reveal robust hierarchical modularity in the genomes of double-stranded DNA viruses. Some of the identified modules combine highly diverse viruses infecting bacteria, archaea, and eukaryotes, in support of previous hypotheses on direct evolutionary relationships between viruses from the three domains of cellular life. We formally identify a set of 14 viral hallmark genes that hold together the genomic network.
Copyright © 2016 Iranzo et al.
The dsDNA virus world as a bipartite network. Nodes corresponding to genomes are…
Core-shell-cloud structure of viral gene…
Core-shell-cloud structure of viral gene families. For each bin, the bar indicates the…
Robustness and cross-similarity of modules…
Robustness and cross-similarity of modules in the virus bipartite network. (A and B)…
Higher-order structure of the virus…
Higher-order structure of the virus network. (A) Bipartite network defined by modules (numbered…
The internal structure of the…
The internal structure of the PL-“Megavirales” supermodule. A module is linked to a…
Internal structure of the Caudovirales…
Internal structure of the Caudovirales supermodule. A module is linked to a connector…
Characterization of viral hallmark genes…
Characterization of viral hallmark genes and module-specific signature genes. (A) All core gene…
Genomes of Single Stranded DNA Viruses and their Mosaicism
Viruses with single stranded DNA genomes infect hosts that belong to all three domains of life and are considered to be economically, medically and environmentally important pathogens. Recent studies have shown that these single stranded DNA viruses exist in great numbers in highly diverse habitats, ranging from extreme geothermal springs to the gut of humans and other animals. International Committee on Taxonomy of Viruses currently classified single stranded DNA viruses into 10 different taxa. However, several viruses that can be classified into additional groups have been isolated and many of their genomes were sequenced. All single stranded DNA viruses are pathogenic on eukaryotes, possess non-enveloped, icosahedral capsids, along with Microviridae family members, which infects bacteria. Single stranded DNA viruses pathogenic on other prokaryotes have filamentous ( Inovirus), rod-shaped ( Plectrovirus), coil-shaped ( Spiraviridae), or pleomorphic (proposed family“Pleolipoviridae”) virions (Table 1.2 ).
Morphological diversity of single stranded DNA viruses
|Host virus taxon||Virion morphology||Genome topology||Genome size|
|Bidnaviridae||Icosahedral||Linear, segmented, 6.5 per segment|
|Geminiviridae||Icosahedral||Circular, segmented 3 per segment|
|Nanoviridae||Icosahedral||Circular, segmented 0.98𠄱.1per segment|
Single stranded DNA viruses are the group comprising of smallest viruses and their genomes are as small as 1𠄲 kb, encoding two proteins one for capsid formation and the other for genome replication. Such irreducible simplicity of single stranded DNA viruses epitomizes their essence of being a virus and makes them an attractive model for investigating virus origins and evolution. Numerous metagenomic studies have revealed a high range of genetic diversity existing in single stranded DNA viruses in the environment, suggesting a highly dynamic interaction between these viruses and their respective hosts. Also, single stranded DNA viruses with the smallest genomes and simplest proteomes were found to be widespread in cellular chromosomes, providing new important insight into the evolution of these viral.
Genomes of Bacteriophages
Bacteriophages are the smallest viruses with simple genomes. Since their discovery in 1915 and 1917 by Fredrick Twort and Felix d’Herelle respectively, bacteriophages have been studied in many laboratories and are being used in a variety of practical applications. The Density of phage viruses present in the oceans is 10 6 7 particles per ml. It was estimated that the total population of the bacteriophages is 10 31 particles and the ratio of environmental virus and bacteria are 5:1, after the validation of 10 30 bacterial cells in the biosphere. Altogether, the prokaryotic population is highly dynamic, with an estimated number of
10 23 global infections per second. It has been hypothesized that oceanic bacteriophages infect bacterial cells at the rate of 10 29 phage infections per day, which releases over 10 11 kg of carbon from the biological pool per day. Over the past three decades, research on bacteriophages has revealed their abundance in nature, genome diversity, impact on the evolution of microbial diversity, their utilization in control of infectious diseases and their influence in regulating the microbial balance in the ecosystem has been explored, leading to a resurgence of interest in the phage research. Research on phages has played a pivotal role in the most significant discoveries, that were made in biological sciences right from the identification of DNA as the genetic material, in the elucidation of the genetic code, leading to the development of the molecular biology. Research on phages has continuously broken new grounds in our understanding of the basic molecular mechanisms of gene expression and their structure. In recent times, phage genomics has revealed novel biochemical mechanisms for replication, maintenance, and expression of the genetic material and is providing new insights into the origins of infectious diseases, utilization of phage gene products and even whole phage as an agent for the gene therapy.
In addition to the killing of bacterial cells, temperate phage genomes also carry toxins and other critical virulence factor genes that are important for many bacterial pathogens to infect human beings. Phages also contribute to the diversity of the bacterial community by serving as vectors for the transduction of different genetic alleles, such as antibiotic resistance genes, between bacterial cells. Phages also have great medical and nanotechnological potential. Strategies for using tailed phages for detecting bacteria, curing bacterial diseases through phage therapy or decontaminating surfaces have been implemented for almost 100 years in Russia and Georgia. These phages are currently being used to treat agricultural diseases as well as in the prevention of food contamination in western countries. Phage virions are being developed as nanocontainers for specific chemical cargoes that can be delivered to specific targets.
Small size and the simplicity of isolation have made bacteriophages as the primary choice for the complete genome sequencing. Phage φX174 is the first organism with the complete genome sequence of 5386 bases of single stranded DNA and λ phage genome is the first organism with double stranded DNA of 48,502p, followed by phage T7 genome of 39,936p. dsDNA tailed mycobacteriophage L5 is the first among non-E. coli phage genomes to be fully sequenced. Further, the sequencing of the bacteriophage genomes are propelled exponentially with two main objectives
To understand the relationship between the phage genomes the evolutionary mechanisms that shaped these bacteriophage populations.
For increased utilization of bacteriophages in the development of tools, utilities, and techniques related to genetics and biotechnology.
Phage genomes display a considerable amount of variation in their size, varying from Leuconostoc phage L5 (2435p) to Pseudomonas phage 201 (316,674). Tailed phages with double stranded DNA genomes vary in their size from 㸐 kbp to 㰕 kbp, consistent with their overall virion structure and gene assembly, which encompass up to 15 kbp of the genome space. of the genome size 1.5𠄶 kbp are characterized by a long flexible non-contractile tail with a tape measure protein gene, whose length corresponds to the phage tail length Many phages with the morphologies similar to Siphoviruses have genomes longer than 20 kbp. Contrastingly, Myoviruses with contractile tails are the phages with larger genomes of kbp and the Bacillus phage SPBc2, is the largest Siphoviral genome of the length 134,416p. The main reason for the absence of large Siphoviruses is still unknown.
Phage Genome Sequence Diversity
Bacteriophages are estimated to be the most widely distributed biological entity of the biosphere. They are found in all habitats of the world, where bacteria proliferate. Most of the viral population is dominated by bacteriophages, with double stranded DNA tailed phages, or Caudovirales, accounting for 95% of all the phages, possibly making up the majority of phages on the planet. However, phages belonging to other groups also occur abundantly in the biosphere, such as phages with different virions, genomes, and lifestyles. Two key approaches were made for studying the viral diversity are metagenomics of total concentrated phage samples collected from the environment and a genome-by-genome strategy of individually isolated phages. These two approaches are compatible, having distinct outcomes. Metagenomics generates a large amount of sequence data, which provides a good insight into their diversity. Sequencing and analysis of individually isolated phages generate small data sets, which are structured into whole genomes. As phage genomes are architecturally mosaic, the availability of complete genomes contextualizes the complexities of their relationships. The nucleotide sequences of phage genomes with non-overlapping hosts rarely share sequence similarity, as noticed in the published genomes of four Streptomyces phages and available collection of 50 mycobacteriophage genomes. Phages infecting a common bacterial host are in genetic contact with each other,ਊnd they share common nucleotide sequences. Genomes of over 30 phages with common host have been isolated and sequenced from Pseudomonas, Staphylococcus, and Mycobacterium containing related sequences, with a few exceptions. Most of these phages share a very low or no sequence similarity, as illustrated by the nucleotide sequence comparisons of mycobacteriophages and Pseudomonas phages .
Genome Mosaicism of Phages
Phages were evolved not only by the accumulation of mutations but also through the recombination events, during which they exchanged genetic material with other phages. These events have been suggested to explain the mosaic structure of the phages, arisen by comparison of two or more phage genomes. During the comparison of the genomes, nearly identical sequences alternate with merely similar sequences or completely divergent sequences. Such type of exchanges in bacteriophages was obtained by heteroduplex mapping in the early 1990s. Since then, numerous mosaics have been identified by sequence comparison, and the mosaic structure of bacteriophages is now a well-documented phenomenon. This mosaicism is also found to be ubiquitous among bacteria, where the genes are acquired through horizontal genetic exchange mostly through transduction, transformation, and conjugation. But, the extent of mosaicism is highly remarkable in phage genomes as evidenced by the increasing number of genomes available for comparative genomics analysis.
The mechanism of genome mosaicism in bacteriophages can be understood at two levels 1. by comparing nucleotide sequence through DNA heteroduplex mapping, 2. by comparing their DNA sequences. There are two models which explain the recombination mechanisms that are responsible for these patterns. Model 1 describes the role of short conserved boundary sequences that are located at gene junctions in targeting various exchange events that are catalyzed by homologous recombinations, by using the recombinases synthesized by either host-or phages. Model 2 attempts to explain that the homologous recombination events are not specifically targeted and occur randomly with the preference of a few short sequences so that most of the events results in non-functional genomic trash. Comparison of the predicted amino acid sequences encoding phage gene products is an alternative manifestation of mosaicism. This is an informative approach, since many phages including those that infect common hosts may not share any nucleotide sequence information. In that case, protein sequence data reveals genes that share much older ancestry.
Genomes of Enterobacteria Phage M13 and λ Phages
M13 Enterobacteria phage infects E. coli. The genome of M13 phage consists of 6.4 kb single-stranded, (+) sense, circular DNA, which encodes for 10 genes. Unlike most icosahedral virions, the capsid of M13 phage is filamentous, which can be expanded by the addition of further protein subunits. Hence, the genome size can also be increased by the addition of extra sequences in the nonessential intergenic region without becoming incapable of being packaged into the capsid (Fig. 1.3 ).
In λ phage, the packaging constraints are much more rigid with DNA of kbp of the normal genome size can be packaged into the virus capsid and the substrate packaged into the phage heads during assembly consists of long concatemers of phage DNA that are produced during the later stages of vegetative replication. The DNA is apparently reeled into the phage head and after the incorporation of the complete genome, DNA is cleaved at a specific sequence by a phage-coded endonuclease, leaving a 12-bp 5¢ overhang on the end of each of the cleaved strands, known as the cos site. Hydrogen bond formation between these ‘sticky ends’ can result in the formation of a circular molecule (Fig. 1.4 ).
In a newly infected cell, the gaps on either side of the cos site are closed by DNA ligase, and resulting circular DNA undergoes vegetative replication and integration into the bacterial chromosome.
The Genome of T4 Phage
Bacteriophages T2 and T4 are the model organisms playing an instrumental role in the development of modern genetics and molecular biology since the 1940s. They were involved in the development of many salient concepts related to biological sciences, including the recognition of nucleic acids as genetic material, identification of a gene through structural, mutational, recombinational, and functional analyses, in the demonstration triplet genetic code, in the identification of mRNA and establishing the importance of recombination in the replication of DNA, in the light-dependent and light-independent DNA repair mechanisms, restriction and modification of DNA, self-splicing introns in prokaryotes, etc. The main advantage of using T4 phage as a model system is its capability of totally inhibiting its host’s gene expression, permitting the investigators to identify the differences between host specific and phage specific macromolecular syntheses. Analysis of the T4 capsid assembly and functioning of its nucleotide-synthesizing complex, replisome, and recombination complexes has led to important insights into macromolecular interactions, substrate channeling, and co-operation between phage and host proteins within such complexes.
The genome of T4 phage is considered as the best avenue for understanding and evaluating the complete genome of a well organized biological system. On the basis of all available information, T4 phage genome comprises of
300 probable genes, packed into a 168,903p genome. This genome comprises 289 expressing genes, 8 tRNA genes, and a minimum of 2 genes that encodes small, stable RNAs with unknown function. Genes 16, 17, and 49 contains multiple coding regions that encode more than one protein. T4 phage genome is four times higher than that of Herpesviruses and yeast, two times higher than E. coli. A very small number of genes contains non-coding regions of
9 kb, accounting for 5.3% of the genome. Regulatory regions in this phage genome are compact, occasionally with overlapping coding regions. Another significant feature of this genome is the overlap of one gene’s termination codon with the start codon of the next one. T4 phage has several groups of nested genes. It was found that only 62 genes in this organism are absolutely essential under standard laboratory conditions (rich medium, aeration, 30 to 37 ଌ). Mutants generated by altering a few other genes produced very small plaques under similar standard laboratory conditions. Many of the 62 essential genes are larger than an average T4 gene, occupying half of the genome. Essential genes encode proteins of the replisome and nucleotide precursor complex, transcriptional regulatory factors, and proteins involved in the structure and assembly of the phage particle. The genome of T4 phage illustrates another rare molecular feature of certain linear viral genomes, terminal redundancy. Replication this phage genome produces long concatemers of DNA, which are cleaved by a specific endonuclease, gets incorporated into the particle with the length exceeding its complete genome due to the repetition of some genes at each end of the genome. Resulting T4 phage genome containing reiterated information is packed into the phage head.
Three T4 phage genes that encode for thymidylate synthase (td), subunit of the aerobic ribonucleotide reductase (nrdB) and the anaerobic ribonucleotide reductase (nrdD) are found to contain introns that are later spliced out of these transcripts. A possibility of an unusual relationship between the nucleic acid sequence and protein sequence occurring through translational bypassing is demonstrated in gene 60 of the T4 phage genome. A 50p mRNA segment in the coding region of this gene is not translated by the regular mechanism. This mRNA segment is the only known and unique high-efficiency translational bypass site in the entire T4 phage genome.
DNA in the genome of this phage contains only 34.5% GC, compared with its host genome of E. coli consisting of 50% GC. In the genome, 18 of the known or predicted genes containing less than 60% AT and 4 predicted genes have less than 58%. Capsid proteins, which are the most widely conserved among the T4-related phages have the lowest AT contents. Gene 23, which encodes for the major head protein, has the lowest AT content of 55%. A substantial decrease in the pairing of G against C in the coding strands of translated regions has been identified. 4 genes having more than 20% C in the coding strand, while more than 130 genes have more than 20% G and 37 genes have more than 22% G. A and T are equally divided between the coding strands. However, some AT bias has been identified in the T4 phage genome, which is stronger in the third position of codons, as expected in genomes with a high amount of AT-rich regions.
Genome size and the oncogenic potential of the DNA viruses
Large double-stranded DNA viruses
As discussed earlier the ability to cause persistent infection depends a lot on the genome size of the DNA viruses. Large double-stranded DNA viruses, therefore, would naturally have the highest oncogenic potential. Since these type of viruses have higher coding capacity due to their larger genomes, they would be able to infect two different cell lineages for two different outcomes. One of the cell lineages would be used for a lifelong infection in the primary host and another cell lineage would be used for lytic infections to spread to the secondary host. What is more important to us is the choice of cells that these DNA viruses prefer for causing persistent infections. Natural selection favours infection of cell types that have favourable traits for viral persistence. It would be revealed in the model later that it is the persistent infection of these high-risk cell lineages that lead to malignant transformation after decades of infection.
Insights from Evolutionary thinking suggest that cells with the following traits would be most suitable for a persistent infection
Most of the cells in the human body have a short limited lifespan and therefore are not a good candidate for persistent infections . Long-lived cells of the immune system can provide ideal shelter for persistent viral infections, as in the case of Epsteinrr virus (EBV), which resides in the resting memory B-cell compartment . The long life of the cell would ensure that the virus inside the cell would survive naturally for a longer time . The terminally differentiated cells of the neurological system are also an ideal candidate for latent infections . Neurons are long-lived, terminally differentiated cells, providing the virus with a virtually everlasting home within the host.
Natural selection could also favour infection of cells that proliferate with higher frequency like Stem cells or lymphocytes. The higher frequency of proliferation would mean that multiple copies of viral genomes are maintained in the body of the primary host.
The third category of cells could have both of these properties i.e. they are long-lived as well as they have a higher frequency of cell division. The persistent infection and subsequent transformation of such cell types would naturally send them at the brink of Cancer.
As per this evolutionary logic, the viruses with large double-stranded DNA genome would be disproportionately associated with Cancer. This category of viruses would have highest oncogenic potential. This is mainly due to the fact that these viruses dysregulate the gene products associated with apoptosis and cell cycle arrest in the cell lineages they infect for persistence . They also interfere with the cellular checkpoints that deal with DNA repair mechanisms . Examples from this family include viruses like EBV that causes Burkitt's lymphoma, Hodgkin's lymphoma, Herpes Simplex 8 that causes Kaposi Sarcoma . The herpes virus family is also widely associated with cancer among animals like cottontail rabbit, Monkeys and Chickens . Another example is mouse cytomegalovirus that infects the cells of salivary glands for acute infections and that of myeloid linkage for latent infections . Other viruses of the Herpes family like Varicella-Zoster virus show latency in the long-lived neurons .
OVERALL MODEL FOR HSV DNA REPLICATION
Initiation of Viral DNA Synthesis
HSV DNA synthesis is believed to initiate at one of the three viral origins of replication, OriL or one of the two copies of OriS with UL9 and ICP8 acting to distort the AT-rich origin spacer region. Complexes containing ICP8 and UL9 can be visualized on negatively supercoiled plasmids containing OriS (Makhov et al. 2003) suggesting that negative supercoiling may facilitate unwinding at the origin. In another in vitro experiment, UL9 and ICP8 were found to unwind an 80-bp double-stranded oligonucleotide containing minimal OriS leading to a model in which UL9 and ICP8 go through a series of conformational changes leading to distortion of an origin. In the first step, two UL9 dimers appear to bind cooperatively to boxes I and II in a second step, UL9, in conjunction with ICP8 in the presence of ATP, can induce the formation of the OriS* hairpin (Aslani et al. 2002 Macao et al. 2004 Olsson et al. 2009). This step is accompanied by conformational changes in UL9 that shift the binding specificity from duplex origin binding to nonspecific ssDNA binding (Macao et al. 2004 Olsson et al. 2009). Because origin binding is specified by the carboxyl terminus and the ssDNA-binding domain requires motif Ia within the amino terminus (Marintcheva and Weller 2003b), the conformational changes in UL9 would be major. The exposure of single-stranded DNA may also cause a conformational change in ICP8 that releases it from UL9 and positions it onto single-stranded DNA where it may act to prevent reannealing of complementary strands. Aspects of this model have been supported by a biophysical analysis of the carboxy-terminal domain of UL9 and a truncated version of ICP8 in complex with a 15-mer double-stranded DNA-containing box I (Manolaridis et al. 2009). This study suggests that a conformational switch of the UL9-binding domain occurs on binding to box I followed by the recruitment of a UL9–ICP8 complex. Several questions remain about how well these in vitro experiments mimic the conditions that arise in an infected cell. Other viral or cellular factors may be required for origin activation on the viral genome in the context of viral infection.
Experiments in infected cells also support the notion that conformational changes in UL9 play critical roles during infection. For instance, UL9 is required at the earliest times post- infection, but appears not to be required at late times. In fact, at late times, UL9 is inhibitory (reviewed in Ward and Weller 2011). The inhibitory properties of UL9 correlate at least in part with its ability to bind to the origins of replication, because inhibition can be relieved by mutations that abrogate DNA binding (Marintcheva and Weller 2003a Chattopadhyay and Weller 2006). Binding of UL9 to the origin of replication is presumably desirable to initiate DNA synthesis but less desirable at later times. Conformational changes in UL9 may be caused by interaction with viral proteins such as ICP8 as described above. Interestingly, other posttranslational modifications of UL9 have also been reported such as phosphorylation and cleavage by cathepsins (Isler and Schaffer 2001 Link et al. 2007). It will be of interest to analyze structural and conformational properties of full-length and truncated versions of UL9 in infected cells to determine the mechanistic basis for the regulation of UL9 during infection.
Once ICP8 and UL9 have initiated the distortion or destabilization at a viral origin as described above, it is thought that the H/P complex is recruited to unwind the duplex DNA and synthesize short RNA primers to initiate DNA replication (Fig. 1A). Aspects of this reaction can be reconstituted in vitro. Recombinant H/P complex can unwind duplex DNA but only if a single-stranded region of at least six nucleotides is provided (Chen et al. 2011). Primase activity can be detected in assays that use a single-strand oligonucleotide as a substrate however, primase activity is inefficient in assays using forked substrates (KL Graves-Woodward and SK Weller, unpubl. KA Ramirez-Aguilar and RD Kuchta, unpubl.). A possible reason for this discrepancy has recently been revealed. Although it has previously been reported that in the absence of DNA, the H/P complex exists as a monomer in solution, electrophoretic shift and surface plasmon resonance analysis have now indicated that in the presence of forked DNA, higher-order complexes can form between the H/P and a forked substrate (Chen et al. 2011). Electrophoretic mobility shift assays reveal two discrete complexes with different mobilities only when H/P is bound to DNA containing a single-stranded region, and surface plasmon resonance analysis confirms larger amounts of the complex bound to forked substrates than to single-overhang substrates. In addition, primase activity shows a cooperative dependence on protein concentration, whereas ATPase and helicase activities do not (Chen et al. 2011). Taken together, these data suggest that the primase activity of the H/P requires formation of a dimer or higher-order structure, whereas ATPase activity does not. As depicted in Figure 1A, the functional form of the H/P complex likely contains at least two copies of the H/P complex.
The last of the herpes replication proteins recruited to the fork appears to be the two-subunit polymerase, Pol and UL42. In infected cells, recruitment of Pol requires the presence of an active primase, indicating that conformational changes that occur in an active H/P complex and/or the RNA primer itself are important to bring the polymerase to viral DNA (Carrington-Lawrence and Weller 2003). Recruitment of polymerase to the fork may involve direct interactions between Pol and the H/P. The UL8 subunit of H/P has been reported to interact with Pol (Marsden et al. 1996). In addition, the UL5 subunit has recently been found to interact with Pol based on coimmunoprecipitation and yeast two-hybrid analysis (P Bai, G Liu, J Liu, et al., in prep.). Once the polymerase complex is recruited to the replication fork, it is believed to catalyze leading- and lagging-strand DNA synthesis however, initial attempts to reconstitute HSV DNA synthesis on primed substrates showed efficient leading-strand synthesis but much less efficient lagging-strand synthesis (Graves-Woodward et al. 1997 Falkenberg et al. 2000). Coupled leading- and lagging-strand DNA synthesis has now for the first time been reconstituted on synthetic minicircular DNA templates with the H/P, ICP8, and the viral polymerase (Pol/UL42) (Stengel and Kuchta 2011). To achieve efficient leading- and lagging-strand synthesis, it was necessary to provide high H/P concentrations and a lagging-strand template whose sequence resembled that of the viral DNA (Stengel and Kuchta 2011). The presence of two H/P complexes at the replication fork may provide a simple mechanism for recruiting two polymerases to the replication fork (Fig. 1B). It is anticipated that this system will facilitate future experiments to examine how other viral and cellular proteins will affect DNA synthesis. It is hoped that eventually it will be possible to develop a system to reconstitute origin-dependent replication.
Formation of Concatemeric DNA
Production of HSV concatemeric DNA is an essential step for the generation of progeny virus as the packaging machinery must recognize longer-than-unit-length concatemers during encapsidation. Although it has been proposed that the viral genome circularizes and rolling circle replication leads to the formation of concatemers, several lines of evidence suggest that HSV DNA replication is more complex and may involve recombination-dependent replication.
By analogy with λ phage, HSV may use viral and/or cellular recombination proteins during DNA replication. Herpesviruses have evolved a complex relationship with host DNA damage response pathways (reviewed in Weitzman and Weller 2011). Several cellular factors involved in double-strand-break (DSB) repair including Mre11, Rad50, Nbs1, and Rad51 are recruited to viral prereplicative sites and replication compartments. Several of these are important for efficient virus production leading to the suggestion that one or more of the DSB repair pathways may be used during HSV infection. Using chromosomally integrated reporter assays designed to distinguish between these pathways, it was found that single-strand annealing (SSA) was increased in HSV-infected cells, whereas homologous recombination (HR), nonhomologous end joining (NHEJ), and alternative nonhomologous end joining (A-NHEJ) were decreased (Schumacher et al. 2012). The increase in SSA was abolished when cells were infected with a viral mutant lacking UL12. Moreover, expression of UL12 alone caused an increase in SSA. UL12 and ICP8 are reminiscent of the λ phage recombination system that has been used as a tool for stimulating recombination-mediated genetic engineering in bacteria (Szczepanska 2009, and references therein). In addition, this system plays an important role in the production of viral DNA concatemers necessary for encapsidation and the production of infectious progeny (Lo Piano et al. 2011). The similarities between λ and HSV DNA replication raise the possibility that concatemer formation during HSV infection involves recombination-dependent replication.
In addition to the UL12/ICP8 viral recombination system and the potential role of the SSA pathway during DNA replication, several other repair pathways have been implicated as required for efficient replication (Muylaert and Elias 2007, 2010 Muylaert et al. 2011). DNA ligase IV/XRCC4 have been reported to be important for efficient virus replication (Muylaert and Elias 2007) suggesting a beneficial role for NHEJ however, in cells deficient for DNA-PK or Ku70, HSV-1 grows better than in their presence suggesting this conclusion may be oversimplified (Parkinson et al. 1999 K Mohni and S Weller, unpubl.). As described earlier, the interaction between the HSV-1 polymerase and HSV uracil-DNA-glycosylase (UL2) may indicate a role for base excision repair (Bogani and Boehmer 2008 Bogani et al. 2009, 2010). Recent reports that MSH2 and MLH1 are required for efficient replication of HSV-1 in normal human cells and are localized to viral replication compartments may indicate a role for mismatch repair in HSV replication (Mohni et al. 2011). Further investigation of the complex relationship between HSV and host repair/recombination pathways will be required to elucidate the role of various repair pathways in HSV DNA replication.
4.11.3: Double-Stranded DNA Viruses - Herpesviruses - Biology
Five DNA viruses are known to cause cancers in humans. These are human papillomavirus, hepatitis B virus, Epstein-Barr virus, Kaposi sarcoma herpes virus and Merkel cell polyomavirus. It is estimated that, together, these are responsible for well over a million new cases of cancer worldwide annually. Also of interest is adenovirus: although it does not cause cancer in humans, it produces malignant tumours in experimental animals. This makes it a very powerful tool to study the mechanisms of viral oncogenesis. In recent years great strides have been made in our understanding of the molecular biology of these DNA viruses, and the virus-host interactions that drive carcinogenicity. These new data are essential first steps in the development of novel therapeutic strategies.
In this timely book, expert authors review the most important current research in this rapidly growing field. Topics covered range from an overview of the contribution of DNA tumour viruses to the cancer burden worldwide, and the molecular pathogenesis of virus driven cancers to vaccine development.
This volume will serve as a valuable reference source for everyone working in the field, both experts and students, in academia, government, and biotechnology companies. It is also a must-read for anyone with an interest in viral tumourigenesis and an important acquisition for all microbiology libraries.
"This book is an excellent, timely current summary of this field and provides further support for the potential clinical application of these studies . the book hits its mark and I would recommend it as a must have . will be of sure interest for anyone want to be informed about cancer related to viral infection." from Human Vaccines and Immunotherapeutics
Despite the great knowledge of the biology of mucosal HR HPV types, additional research is needed to characterize the biology of the majority of HPV types that have been poorly investigated so far, with a final aim of evaluating their potential roles in other human diseases.
(EAN: 9781910190791 9781910190807 Subjects: [medical microbiology] [molecular microbiology] [virology] )
To determine the structure of the unique 5-fold vertex comprising the portal and portal-vertex–associated tegument (PVAT), we imaged purified HSV-1 virions by cryoEM (S1 Fig). A total of 3,702 micrographs were captured, from which a dataset of 6,069 virion images was extracted for 3D reconstruction. An initial 3D reconstruction was calculated with full icosahedral symmetry imposed in order to accurately define the particle origins and orientations in each image (Fig 1a). The icosahedral reconstruction achieved a resolution of 6.3 Å (S2 Fig, S1 Data) and closely resembled recently published structures at a similar resolution, revealing well-defined CATC density with a clear five-helix bundle that has been shown to comprise helices donated by a single copy of pUL17, two copies of pUL25, and two copies of pUL36 (Fig 1d and 1e) [5,32]. At lower isosurface threshold, we see two distinct globular domains per CATC, one on top of the pentonal pUL19 and one lying to the side. These densities have been shown to be the C-terminal domain of pUL25 thus, there are 10 pUL25 molecules per 5-fold vertex (Fig 1c) .