27 Jun 2022
Issue #111: Virus persistence and Long COVID interface with herpesvirus reactivation
Written by Nobel Laureate Professor Peter Doherty
While some manifestations (#110) of Long COVID (LC) are likely a consequence of organ damage following severe disease requiring hospitalization (PHLC), the LC syndrome seen in people who develop chronic clinical impairment after a relatively mild initial course (IMLC) is suggestive of an ongoing, active process.
An obvious possibility is that SARS-CoV-2 virions (virus particles) are persisting somewhere in the body and continue to kill (or compromise the function of) physiologically important cells. Another idea is that much of the characteristic IMLC symptomatology is a side effect of unsuccessful ‘over-the-top’ efforts by the ‘adaptive’ virus-specific immune response to eliminate either persistent SARs-CoV-2, or some subviral component of the pathogen.
All viruses consist of an information system - encoded in the nucleic acid base pairs (bps) of RNA or DNA - packaged in a protective layer of protein and attached carbohydrates (sugars). In addition, SARS-CoV-2 is an enveloped virus, with an outer lipid (fat) envelope. These sugars and fats are unlikely to cause problems, so any ongoing pathology would likely be associated with either continued virus production, or the presence of viral proteins or peptides (protein breakdown products) that are just ‘hanging around’ in some form. The same argument applies to persistent viral RNA that encodes for the production (perhaps intermittent) of one or other SARS-CoV-2 protein. This will be our focus for the next few weeks.
We’ll start by discussing some other viruses that are notorious for ‘hiding out for life’ in our bodies. The herpesviruses (HVs) are big DNA viruses with evolved molecular mechanisms for establishing as ‘silent’, or latent, infections where viral genome is preserved but no – or little -protein (or peptide) is being made. We’ve lived with the HVs for millennia, and it is I think reasonable to assume that they have influenced the development of our immune system, while we in turn shaped them. Unless we are severely immunosuppressed by, say, whole body irradiation or cancer treatment with cytotoxic drugs, these ‘intimate pathogens’ can be silent, or cause periodic discomfort, but they don’t usually kill us.
The 158 kb herpes simplex virus type 1 (HSV1) infects via the lip (a loving kiss in infancy) to cause an acute, severe inflammatory lesion that quickly resolves as our immune system eliminates the pathogen from that site. In the meantime, the virus has moved up the nerve fibres (axons) to the trigeminal ganglion in the face to invade the cell body of one or more sensory neurons, where it establishes in a ‘latent’ form. When the lip is later traumatized - by sunburn or abrasion while sneezing during an URTI (upper respiratory tract infection) - locally-produced danger/damage signals (cytokines/chemokines) use the same axonal ’retrograde flow’ pathway to reactivate HSV in the nerve cell body. The virus then travels back down to the lip and the whole cycle is repeated. Most of us are familiar with the occasional discomfort of a cold sore and keep an appropriate lip ointment (such as Acyclovir, a nucleoside analogue that blocks viral replication) to hand. But even without that, the cold sore experience of transient local pain and dysfunction is quite different from what people with IMLC are experiencing. In the same category, but much more distressing can be the recurrent genital lesions caused by both HSV1 and HSV2. Here, viral latency establishes in the local, sacral ganglia or the dorsal root ganglia (DRG) of the spinal cord.
The other herpesvirus that ‘hides’ in the DRG is varicella zoster virus (VZV), which causes chickenpox in children, and that can reactivate decades later to trigger shingles in the elderly. There are now good VZV vaccines to prevent chickenpox and to boost our failing immune systems as we age so that we don’t develop shingles, an extremely painful condition that occurs across a whole skin segment (a dermatome) innervated from a single DRG.
Both cold sores and shingles can, it seems, be reactivated in some of us by SARS-CoV-2 infection. Whether this is a direct effect (a possibility with cold sores) or due to some broader immunosuppression is not clear. Making vaccines against both HSV1 and HSV2 has proven to be difficult, but there is some hope that the new mRNA vaccine technology first used for COVID-19 may be the key to success, especially if that could be extended to another herpesvirus that is both more mysterious and of major concern: Epstein Barr virus (EBV).
If we do a PCR test for EBV genome on throat or mouth swabs, most adults are EBV positive, indicating that Epstein Barr virus may be both latent and ‘grumbling away’. That’s even more the case for another ubiquitous human herpesvirus, cytomegalovirus (CMV) which can be a major problem for people who have a bone marrow transplant.
A first encounter with EBV in adolescence is classically associated with infectious mononucleosis, or ‘kissing disease’, a condition characterized by massively increased white blood cell (WBC) counts and extreme lethargy. Most young patients recover within two to four weeks, but some suffer for months or even years with manifestations of chronic fatigue syndrome (CFS). One theory of LC is, indeed, that at least some cases could be due to EBV reactivation: CFS and LC are identical in many respects. However, though there is evidence of both EBV and CMV reactivation in SARS-CoV-2 infection, this seems to be more associated with severe disease in the acute phase, rather than the LC manifestation of COVID-19.
To be continued...