Non-cytolytic enterovirus

NOTE: This page is currently under construction.

Introduction
Non-cytolytic enterovirus infection is an aberrant form of viral infection that enterovirus B species such as coxsackievirus B can transmute into within the host. Evidence for the existence of this form of infection dates back to at least 1990, but an understanding of the molecular mechanism of non-cytolytic enterovirus has only been obtained in recent years.

The transformation of normal lytic enterovirus into the non-cytolytic form is underpinned by deletions in the genome the virus acquires in the host. This altered form of enterovirus may then cause persistent intracellular infections which replicate very slowly without killing the cells. Non-cytolytic enterovirus infections have been shown to lead to cellular dysfunction, and may affect immune signaling, induce autoimmunity, or elicit a pro-inflammatory immune response. Non-cytolytic enterovirus is difficult for the immune system to eradicate, so it can persist for very long periods, and is associated with a range of chronic diseases.

Persistent enteroviral infections have been found in: The persistent enterovirus infections found in the above diseases are in several cases (those shown in italics) explicitly demonstrated to be non-cytolytic.
 * The brain, muscle and stomach tissues of myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) patients; see enterovirus infection studies.
 * The heart muscle in murine and human coxsackievirus B (CVB) chronic myocarditis.
 * The heart muscle in dilated cardiomyopathy (a sequelae of myocarditis).
 * The skeletal muscles in murine and human chronic myositis.
 * The cerebrospinal fluid and spinal cord tissue of amyotrophic lateral sclerosis (a motor neuron disease).
 * The brainstem in Parkinson's disease.
 * The salivary gland epithelial cells and lymphocyte infiltrates in primary Sjögren's syndrome.
 * The cerebrospinal fluid in post-polio syndrome.
 * The murine pancreas and human pancreas, which has implications for type 1 diabetes.

Several researchers including Prof Nora Chapman, Prof Steven Tracy and Dr John Chia theorize that it is specifically the non-cytolytic form of enterovirus infection may cause ME/CFS. Persistent enterovirus is also being investigated as a possible cause for the other above-listed diseases as well.

Note: non-cytolytic enterovirus is also referred to as: non-cytopathic enterovirus, defective enterovirus, and terminally deleted enterovirus.

The nature of non-cytolytic infection
When enterovirus is initially contracted by a host, it begins as a normal acute lytic infection. Lytic infection involves the virus entering into host cells and replicating rapidly, producing tens of thousands of new viral particles (virions) in each infected cell, then killing the cell through lysis, allowing the new virions to escape and infect more cells.

But during such acute infections, enterovirus B serotypes such as coxsackievirus B are capable of transforming inside infected host cells into the aberrant non-cytolytic form. Non-cytolytic infections are not a different species of enterovirus; they arise from regular enterovirus B species in common circulation, but which under certain circumstances, can get converted in the host to the non-cytolytic form. This transformation is due to natural mutations (deletions) that appear in the viral genome during viral replication in host cells, and which give rise to the non-cytolytic virus, an enterovirus quasispecies with a dramatically altered virus lifecycle.

Whereas the lifecycle of a lytic enterovirus centers on the virion, once this is transformed to a non-cytolytic infection, the virus then exists as strands of naked viral RNA that reside within the host cell. This 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.

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). The latter is formed when the positive ssRNA and negative ssRNA in the cell join to create dsRNA. The genome mutations of the non-cytolytic viral RNA differentiate it from the lytic virus RNA, which has an intact genome.

Non-cytolytic infections rarely produce lytic virions (infectious virions with an intact genome), neither in myocarditis or dilated cardiomyopathy, nor myositis, nor ME/CFS. This infection can nevertheless propagate by packing its defective genomes into capsids (viral shells) to create virions; this allows the non-cytolytic infection to spread.

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 and propagates, albeit very slowly.

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 use to create a persistent presence in the host. But it is now clear enterovirus can form chronic low-level infection as a non-cytolytic virus and can persist even in immunocompetent hosts for very long periods.