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Non-cytolytic enterovirus
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== The nature of non-cytolytic infection == When enterovirus is initially contracted by a host, it creates an acute lytic infection. Lytic infection involves the virus entering into host cells and replicating rapidly, producing thousands of new viral particles ([[Virion|virions]]) in each infected cell, then rupturing and killing the cell through [[lysis]], allowing the new virions to escape and infect more cells. The immune response will clear such acute infections from the host within weeks. Until relatively recently, enterovirus was thought only capable of acute lytic infection; it was not generally believed to cause chronic infection.<ref name="Kim2005-6" /><ref name="Flynn2017">{{Cite journal | last = Flynn | first = Claudia T. | last2 = Kimura | first2 = Taishi | last3 = Frimpong-Boateng | first3 = Kwesi | last4 = Harkins | first4 = Stephanie | last5 = Whitton | first5 = J. Lindsay | date = Dec 2017 | title = Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> However, it is now clear that during the first weeks of acute infection, enterovirus B serotypes can sometimes transmute into the non-cytolytic form — a form which can then go on to create persistent infections in the host.<ref>{{Cite web|url=https://www.youtube.com/watch?v=3Ro7UlhSD-w&t=10m00s | 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 10:10 | last = Chapman | first = Nora | date = 2008 | website = YouTube | archive-url=|archive-date=|url-status=|access-date=}}</ref> This form is so named because cell destruction by lysis is rarely seen in the cells it infects. The conversion from lytic to non-cytolytic enterovirus results from certain mutations (deletions at the end of the viral genome) which may manifest during the acute phase.<ref>{{Cite web|url=https://www.youtube.com/watch?v=3Ro7UlhSD-w&t=3m11s | 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 3:11. | last=Chapman | first = Nora | date = 2008 | website = YouTube | archive-url=|archive-date=|url-status=|access-date=}}</ref><ref name="Chapman2008a" /> Once these mutations occur, it changes the capabilities of the virus, producing a modified pathogen that is now able to evade the immune system, and form persistent infections. Non-cytolytic infections are not a different species of enterovirus; they arise from regular enterovirus B serotypes in common circulation, but which as a result of these mutations get transmuted into a distinct quasispecies. Viral quasispecies are viruses which within the host have acquired small mutations in their genome, but which are still closely related to their parent virus. In the case of non-cytolytic enterovirus, these acquired mutations lead to a dramatically altered virus lifecycle.<ref name="Kim2005b">{{Cite journal | last = Kim | first = K.-S. | last2 = Tracy | first2 = S. | last3 = Tapprich | first3 = W. | last4 = Bailey | first4 = J. | last5 = Lee | first5 = C.-K. | last6 = Kim | first6 = K. | last7 = Barry | first7 = W.H. | last8 = Chapman | first8 = N.M. | date = Jun 2005 | title = 5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11 | pages = 7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=These results represent the first report of an in vivo evolution of a wild-type enterovirus population into a quasispecies that has 5′-terminal genomic deletions ranging from 7 to 49 nucleotides.|via=}}</ref> The lifecycle of a regular lytic enterovirus centers on the virion, but once transformed to a non-cytolytic infection, the virus then exists in a very different configuration: as strands of naked viral RNA that reside within host cells creating a persistent intracellular RNA infection. This intracellular viral RNA is self-replicating and self-sustaining, and is thought can survive independently of any help from the lytic infection. Furthermore, whereas the lytic virus destroys by lysis the cells it infects, non-cytolytic enterovirus does not typically kill the host cells it inhabits, allowing the non-cytolytic infection to reside in these cells on a long-term basis. <br />[[File:Lytic and noncytolytic enterovirus infection.png|frameless|900x900px]] The self-sustaining RNA infection of non-cytolytic enterovirus consists of positive and negative [[single-stranded viral RNA]] (ssRNA), as well as [[double-stranded viral RNA]] (dsRNA).<ref name="Tam1999b">{{Cite journal | last = Tam | first = P. E. | last2 = Messner | first2 = R.P. | date = Dec 1999 | title = Molecular mechanisms of coxsackievirus persistence in chronic inflammatory myopathy: viral RNA persists through formation of a double-stranded complex without associated genomic mutations or evolution | url =https://www.ncbi.nlm.nih.gov/pubmed/10559326/|journal=Journal of Virology|volume=73|issue=12|pages=10113–10121|issn=0022-538X|pmid=10559326|quote=By 1 month after infection, which is a time when infectious virus can no longer be recovered, the level of plus-strand RNA in muscle had diminished to a fourfold excess over minus-strand RNA. Given the slightly higher efficiency for RT-PCR of the plus-strand RNA, actual levels of plus- and minus-strand RNAs were nearly equal. Moreover, the RNA appeared to persist as a double-stranded complex, and absolute levels of minus-strand RNA were similar to those which were present during acute infection.|via=}}</ref> The latter is formed when the positive ssRNA and negative ssRNA in the cell join to create dsRNA. Non-cytolytic infections very rarely produce lytic virions (infectious virions with a complete genome), neither in chronic myocarditis nor dilated cardiomyopathy<ref name="Archard1987">{{Cite journal | last = Archard | first = L. C. | last2 = Richardson | first2 = P.J. | last3 = Olsen | first3 = E.G. | last4 = Dubowitz | first4 = V. | last5 = Sewry | first5 = C. | last6 = Bowles | first6 = N.E. | date = 1987 | title = The role of Coxsackie B viruses in the pathogenesis of myocarditis, dilated cardiomyopathy and inflammatory muscle disease|url=https://www.ncbi.nlm.nih.gov/pubmed/2847741|journal=Biochemical Society Symposium|volume=53 | pages = 51–62|issn=0067-8694|pmid=2847741|quote=despite many attempts, isolation of infectious virus or immunofluorescent detection of virus-specific antigens in the affected tissue is rare|via=}}</ref><ref name="Rey2001">{{Cite journal | last = Rey | first = L. | last2 = Lambert | first2 = V. | last3 = Wattré | first3 = P. | last4 = Andréoletti | first4 = L. | date = Jun 2001 | title = Detection of enteroviruses ribonucleic acid sequences in endomyocardial tissue from adult patients with chronic dilated cardiomyopathy by a rapid RT-PCR and hybridization assay|url=https://www.ncbi.nlm.nih.gov/pubmed/11360245|journal=Journal of Medical Virology|volume=64|issue=2|pages=133–140|issn=0146-6615|pmid=11360245|quote=Of the 55 biopsy specimens aseptically collected from the explanted hearts of 55 patients, 21 (38.2%) were positive by RT-PCR microplate assay, whereas only 19 (34.5%) were positive by nested RT-PCR assay and none were positive by classical cell culture assays.|via=}}</ref> nor [[ME/CFS]].<ref name="Cunningham1991">{{Cite journal | last = Cunningham | first = L. | last2 = Bowles | first2 = N.E. | last3 = Archard | first3 = L.C. | date = Oct 1991 | title = Persistent virus infection of muscle in postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1665379|journal=British Medical Bulletin|volume=47|issue=4 | pages = 852–871|issn=0007-1420|pmid=1665379|quote=Attempts to demonstrate either infectious virus or virus-specific antigens in muscle samples from PVFS patients had been consistently unsuccessful.|via=}}</ref><ref name="ChiaChia2008" /> Non-cytolytic infection can nevertheless propagate by packing its defective genomes into capsids (viral shells) to create virions; this is one way the defective virus can spread.<ref>{{Cite web|url=https://www.youtube.com/watch?v=3Ro7UlhSD-w&t=6m57s | 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 6:57. | last=Chapman | first = Nora | date = 2008 | website = YouTube | archive-url=|archive-date=|url-status=|access-date=}}</ref> Note that the non-cytolytic state of enterovirus is distinct from viral latency: in the latent state, viruses are typically dormant for long periods and do not engage in viral replication or viral propagation; whereas a non-cytolytic infection actively replicates (albeit very slowly) and propagates. RNA viruses such as enterovirus are generally not capable of latency (usually only DNA viruses are able to go into latency). So latency is not a mechanism that enterovirus could employ to create a persistent presence in the host. But it is now clear enterovirus can form a chronic low-level intracellular infection as a non-cytolytic defective virus and can persist in immunocompetent hosts for very long periods.<ref>{{Cite web|url=https://www.youtube.com/watch?v=3Ro7UlhSD-w&t=13m46s | 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 13:46. | last=Chapman | first = Nora | date = 2008 | website = YouTube | archive-url=|archive-date=|url-status=|access-date=}}</ref>
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