Issue #114: Persistence of SARS-CoV-2 and Long COVID 2: Defective virus, privilege & pathology

Written by Nobel Laureate Professor Peter Doherty

Any clinical consequences of acute infections with RNA viruses like influenza (#46), measles, Japanese encephalitis (#99) and so forth generally start to resolve after the ‘effectors’ of adaptive immunity, the circulating antibodies (or immunoglobulins, Igs) and the immune T cells come into play to eliminate both the virus (#21, #22) and the virus-producing ‘factory’ cells (#33, #34). Using the traditional techniques of virology - like the isolation of infectious virions in tissue culture (#113) - the perception was that these pathogens have pretty much gone from our bodies by the time we are feeling better. But, with more recent technology based on, particularly, the detection of viral RNA, we now know that this can be too simple a view.

One situation we’ve long been aware of is the potential for the persistence of defective viral genomes (DVGs) in ‘immunologically privileged sites’ (IPS). The term IPS refers to body organs, like the clinically normal brain and eye, that are to some extent ‘protected’ from the immune surveillance function that detects the local presence of a ‘foreign invader’. The best-known example of a DVG causing severe disease is when a hypermutated variant of measles virus (a morbillivirus) that lacks the capacity to make the M protein required to form fully infectious virions suddenly emerges from hiding to cause subacute sclerosing panencephalitis (SSPE).

Typically, from seven to ten years after experiencing measles in childhood, a normal adolescent may suddenly develop severe headaches and a lack of capacity to concentrate. Over the next one to three years, this may progress inexorably to either a fatal outcome, or to a permanent vegetative state. A few may recover, to a greater or lesser extent. A rare disease, the development of SSPE is thought to reflect the reactivation of the measles DVG that, in turn, triggers protein production and the massive invasion and localisation of inflammatory cells, including antibody secreting plasma cells. A characteristic feature is the presence of high levels of measles-specific IgG in cerebrospinal fluid (CSF). SSPE almost disappeared from advanced countries like the USA following the introduction of universal measles vaccination, though there are concerns associated with the increasing prevalence of vaccine refusal. 

Measles virus and SARS-CoV-2 are RNA viruses that use very different replication strategies, though it is the case that DVGs can also be produced in coronavirus infections. While there are no indications to date that an SSPE-like syndrome could be a long-term consequence of COVID-19 there is, however, some evidence that severe SARS-CoV-2 infection can sometimes trigger another central nervous system (CNS) problem, demyelination, the pathological change characteristic of human multiple sclerosis (MS). Both clinical cases of canine distemper (caused by a morbillivirus) and experiments with mouse hepatitis virus (a b CoV like SARS-CoV-2) have long been of interest to MS researchers because of the demyelination that can result from these infections. https://pubmed.ncbi.nlm.nih.gov/15645260/ and https://www.frontiersin.org/articles/10.3389/fncel.2015.00488/full

Produced by specialised cells called oligodendrocytes, myelin is a lipoprotein sheet that wraps around the nerve fibres (axons) and serves as an insulating layer to facilitate rapid signal transmission. Primary (due, for example, to the death of oligodendrocytes) or secondary (as a consequence of direct axonal/white matter damage) demyelination can potentially be an ‘innocent bystander’ consequence of severe inflammation in the brain. Neuronal or oligodendrocyte loss leading to demyelination could also result from the reactivation of our old friends, the HHVs (#111, #112) that are, at times, known to cause active infections in the brain. Both HSV1 and HHV6 have been implicated, while a recent analysis of US military personnel showed a strong link between EBV infection and MS. 

Our body organs respond to damage in stereotyped ways, so the fact that various viruses that cause both cell death and inflammatory damage can lead to a shared, final pathology is not surprising. The capacity for neuronal repair after an acute CNS virus infection is limited. So far, SSPE is a special case that’s only linked to measles virus in the IPS of the brain.  Otherwise, DVGs that tend to emerge late in an acute infection may tend to promote stronger immunity and (unless in an IPS) be eliminated along with other viral components.

Discussing the (hopefully unlikely) possibilities of an SSPE- or MS-like disease emerging years after an experience of COVID-19 raises an important point about this pandemic. There’s long been speculation that apparently ‘autoimmune’ conditions like MS and rheumatoid arthritis could have been triggered by some remote, unknown virus infection of childhood or adolescence. Now, with COVID-19 we have, for the countries that keep comprehensive medical records at least, a specific, timed diagnosis (by PCR) of SARS-CoV-2 infection for very large numbers of individuals. That diagnosis clearly needs to be preserved as part of our medical histories. For the future, especially as we continue with personalised genomics, having this information could be of immense value.

 Returning to Long COVID (LC), the ‘brain fog’ that is currently associated with the type of LC seen after a relatively mild initial experience of COVID-19 does not obviously resemble MS or SSPE, though it’s possible that elements of such pathology could be a factor in the LC ‘symptoms complex” for patients who survive hospitalisation and an ICU stay (#110). We’ll look more closely at the ‘brain fog’ problem later.