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Non-cytolytic enterovirus
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==How does lytic enterovirus transmute into the non-cytolytic form? == The mechanism by which lytic (wild-type) enterovirus can get transformed into a non-cytolytic virus within the host was identified by Prof [[Nora Chapman]] in a landmark 2005 study.<ref name="Kim2005a" /> Chapman says that the conversion of acute lytic enterovirus into a non-cytolytic infection can only occur in specific cell types, namely in non-dividing quiescent cells (such as [[muscle]] cells), but cannot occur in dividing cells (like [[liver]] cells). A certain amount of non-cytolytic enterovirus RNA is always generated during lytic replication, through random mutations from replication errors; but in dividing cells, because production of lytic virus is efficient, lytic virus populations dominate over non-cytolytic populations, and the cell thus is co-opted for lytic replication. By contrast, in quiescent cells, due to specific cellular conditions, lytic virus manufacture is very inefficient, and this provides an opportunity for non-cytolytic populations in quiescent cells to grow and prevail. Once non-cytolytic virus establishes itself as the dominant species in the cell, it co-opts the cell for non-cytolytic replication. This transmutation of lytic into non-cytolytic enterovirus occurs during acute infection, in a timeframe in the order of weeks after the virus is first caught. This is the essence of how non-cytolytic enterovirus infection is born, but we now explain in detail how this transmutation from lytic to non-cytolytic virus occurs. In the mechanics of lytic enterovirus infection, viral negative single-stranded viral RNA (ssRNA) is employed as a template to create numerous positive ssRNA copies (like a photographic negative producing lots of prints). The positive ssRNA copies are then packed into capsids (viral shells) to make new enterovirus virions. Enteroviruses are positive single-stranded RNA viruses, meaning their genome comprises positive ssRNA; so in order to create thousands of new enterovirus virions, thousands of copies of the positive ssRNA are required. <br />[[File:Lytic enterovirus infection in a rapidly dividing cell.png|frameless|900x900px]] When enterovirus enters a rapidly dividing cell, it efficiently produces thousands of copies of positive ssRNA with the help of an important factor present in the cell known as hnRNP C ([[heterogeneous nuclear ribonucleoprotein C]]). This factor works by binding to the negative ssRNA, where it has the effect of accelerating production of positive ssRNA.<ref>{{Cite journal | last = Lévêque | first = Nicolas | last2 = Garcia | first2 = Magali | last3 = Bouin | first3 = Alexis | last4 = Nguyen | first4 = Joseph H.C. | last5 = Tran | first5 = Genevieve P. | last6 = Andreoletti | first6 = Laurent | last7 = Semler | first7 = Bert L. | date = 2017-08-15 | title = Functional Consequences of RNA 5'-Terminal Deletions on Coxsackievirus B3 RNA Replication and Ribonucleoprotein Complex Formation | url =https://www.ncbi.nlm.nih.gov/pubmed/28539455|journal=Journal of Virology|volume=91|issue=16|pages=|doi=10.1128/JVI.00423-17|issn=1098-5514|pmc=5533909|pmid=28539455|quote=It is known that the host protein hnRNP C can bind both the 3′ and 5′ termini of poliovirus negative-strand RNA intermediates, an interaction proposed to promote the synthesis of positive-strand enterovirus RNA molecules. Thus, the 5′-terminal deletions of positive-strand RNAs would lead to deletions in the 3′ ends of negative-strand RNAs, possibly reducing the binding of hnRNP C to these replication intermediates. Loss of such binding might also contribute to the reduction of positive-strand RNA synthesis observed with TD viruses.|via=}}</ref> With the aid of hnRNP C, each strand of enterovirus negative ssRNA is able to efficiently produce around 100 strands of positive ssRNA. So in rapidly dividing cells, a 100-fold excess of positive strands over negative strands is observed. However, in a quiescent cell, the factor hnRNP C is not available to the virus, as this factor is confined to the cell nucleus when cells are not dividing. Only when a cell starts dividing ([[mitosis]]) does hnRNP C move into the [[cytoplasm]] (the region between the nucleus and the cell membrane), where enterovirus replicates. Without the assistance of hnRNP C, positive ssRNA production is severely impacted, and now each negative ssRNA template is only able to manufacture in the order of 1 strand of positive ssRNA. In consequence, roughly equal numbers of positive and negative ssRNA strands are observed in quiescent cells. Because of the great shortfall of positive ssRNA in quiescent cells, very few lytic virions are created. As a result, cellular lysis — the destruction of the cell as the virions are released — does not occur. Instead the cell survives, and is populated with roughly equal amounts of enteroviral positive and negative ssRNA. With these conditions found in quiescent cells, a non-cytolytic enterovirus infection can emerge. The emergence pivots on natural defects appearing in the viral genome. In viral replication, during the synthesis of viral RNA, reproduction errors naturally arise; these errors will often be in the form of deletions in the 5′ (pronounced "five primed") region at the terminal end of the genome ([[wikipedia:Five_prime_untranslated_region|5′ is an untranslated region]] at the end of the genome). These deletions just result from premature termination of the process of genome transcription.<ref>{{Cite web|url=https://www.youtube.com/watch?v=3Ro7UlhSD-w&t=4m00s | title = How Does a Lytic Enterovirus Persist and Cause Chronic Disease? Enterovirus Session, International Symposium on Viruses in CFS & Post-viral Fatigue, Maryland, US, June 2008. Timecode: 4:00. | last=Chapman | first = Nora | date = 2008 | website = YouTube | archive-url=|archive-date=|url-status=|access-date=}}</ref> Now it just so happens that these deletions in the 5′ region are located in precisely the part of the genome that hnRNP C binds to on the negative ssRNA template.<ref>{{Cite web|url=https://www.youtube.com/watch?v=3Ro7UlhSD-w&t=5m38s | title = How Does a Lytic Enterovirus Persist and Cause Chronic Disease? Enterovirus Session, International Symposium on Viruses in CFS & Post-viral Fatigue, Maryland, US, June 2008. Timecode: 5:38. | last=Chapman | first = Nora | date = 2008 | website = YouTube | archive-url=|archive-date=|url-status=|access-date=}}</ref> Thus once the deletions occur in the virus, this genomic defect permanently prevents efficient production of positive ssRNA. So now, not only do we have a cell which being quiescent lacks cytoplasmic hnRNP C, but this situation is compounded by the deletions in the viral genome, which prevent hnRNP C binding to the negative strand template. Under these conditions, lytic virus creation greatly inhibited, and the replication process starts duplicating the genomes containing deletions, ie, duplicating the non-cytolytic virus. These circumstances favor the evolution and domination of non-cytolytic enterovirus,<ref>{{Cite journal | last = Lévêque | first = Nicolas | last2 = Garcia | first2 = Magali | last3 = Bouin | first3 = Alexis | last4 = Nguyen | first4 = Joseph H.C. | last5 = Tran | first5 = Genevieve P. | last6 = Andreoletti | first6 = Laurent | last7 = Semler | first7 = Bert L. | date = 2017-08-15 | title = Functional Consequences of RNA 5'-Terminal Deletions on Coxsackievirus B3 RNA Replication and Ribonucleoprotein Complex Formation | url =https://www.ncbi.nlm.nih.gov/pubmed/28539455/|journal=Journal of Virology|volume=91|issue=16|pages=|doi=10.1128/JVI.00423-17|issn=1098-5514|pmc=5533909|pmid=28539455|quote=Moreover, low levels of hnRNP C expression in the cytoplasm of quiescent and differentiated cells (like cardiomyocytes) have been suggested to give putative hnRNP C-independent TD genomes an evolutionary advantage over hnRNP C-dependent wild-type enterovirus RNA, thereby enabling them to become the dominant virus population in persistent infections.|via=}}</ref> and lead to the creation of a non-cytolytic infection. [[File:Noncytolytic enterovirus infection in a quiescent cell.png|frameless|900x900px]] This transmutation of lytic into non-cytolytic infection by means of genome deletions cannot occur in a dividing cell, because although viral replication in dividing cells produces RNA with the same genomic deletions, these deleted genomes are outnumbered by the high amounts of lytic virions efficiently generated, thanks to hnRNP C. And furthermore, during lytic virus production in a dividing cell, the process rapidly kills the cell by lysis, so the deleted genome RNA infection has nowhere to live. Thus conversion to the non-cytolytic form is thought possible only in quiescent cells. Deletions in the 5′ terminal end of the viral genome in persistent low-level coxsackievirus B infections were first detected by Nora Chapman and colleagues in the 2005 study,<ref name="Kim2005a" /> and have since been demonstrated in subsequent studies.<ref>{{Cite journal | last = Bouin | first = Alexis | last2 = Nguyen | first2 = Yohan | last3 = Wehbe | first3 = Michel | last4 = Renois | first4 = Fanny | last5 = Fornes | first5 = Paul | last6 = Bani-Sadr | first6 = Firouze | last7 = Metz | first7 = Damien | last8 = Andreoletti | first8 = Laurent | date = Aug 2016 | title = Major Persistent 5' Terminally Deleted Coxsackievirus B3 Populations in Human Endomyocardial Tissues|url=https://www.ncbi.nlm.nih.gov/pubmed/27434549/|journal=Emerging Infectious Diseases|volume=22|issue=8|pages=1488–1490|doi=10.3201/eid2208.160186|issn=1080-6059|pmc=4982168|pmid=27434549}}</ref><ref name="Chapman2008a" /><ref name="Kim2008">{{Cite journal | last = Kim | first = K.-S. | last2 = Chapman | first2 = N.M. | last3 = Tracy | first3 = S. | date = Feb 2008 | title = Replication of coxsackievirus B3 in primary cell cultures generates novel viral genome deletions|url=https://www.ncbi.nlm.nih.gov/pubmed/18057248/|journal=Journal of Virology|volume=82|issue=4|pages=2033–2037|doi=10.1128/JVI.01774-07|issn=1098-5514|pmc=2258713|pmid=18057248}}</ref> The deletions range from 7 to 49 nucleotides in length<ref name="Kim2005b" /> (by comparison the full coxsackievirus B genome comprises around 7,400 nucleotides).<ref name="Leveque2017b" /> Lévêque et al<ref name="Leveque2017b">{{Cite journal | last = Lévêque | first = Nicolas | last2 = Garcia | first2 = Magali | last3 = Bouin | first3 = Alexis | last4 = Nguyen | first4 = Joseph H.C. | last5 = Tran | first5 = Genevieve P. | last6 = Andreoletti | first6 = Laurent | last7 = Semler | first7 = Bert L. | date = 2017-08-15 | title = Functional Consequences of RNA 5'-Terminal Deletions on Coxsackievirus B3 RNA Replication and Ribonucleoprotein Complex Formation | url =https://www.ncbi.nlm.nih.gov/pubmed/28539455|journal=Journal of Virology|volume=91|issue=16|pages=|doi=10.1128/JVI.00423-17|issn=1098-5514|pmc=5533909|pmid=28539455|quote=Interestingly, Hyde and colleagues demonstrated that alphaviruses, which are also single-stranded, positive-strand RNA viruses, use mutations within the 5′ noncoding region affecting secondary-structural elements of their RNAs to alter interferon-stimulated protein binding and functions. Their results suggest an evasion mechanism by which a deleted virus with modified 5′ RNA secondary structures could avoid immune restriction, despite type 1 IFN secretion and interferon-stimulated gene transcription, leading to long-term virus persistence in the heart.|via=}}</ref> speculate that these genome deletions might also facilitate immune evasion, thereby making non-cytolytic enterovirus largely invulnerable to immune clearance. So this is the mechanism and conditions by which non-cytolytic enterovirus infection is born, and once this intracellular infection is created, it is observed that the immune system cannot easily clear it.
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