04 Jul 2022
Issue #112: Virus persistence and Long COVID: DNA and RNA viruses
Last week, we looked at the ubiquitous herpesviruses (HVs) – large DNA viruses that are known to persist for life in us, to ask whether at least some of the manifestations of Long COVID (LC) might reflect HV reactivation during SARS-CoV-2 infection (#111). It is indeed the case that both the incidence of obvious HV-induced (#111) clinical manifestations, like cold sores (HSV1) or shingles (VZV), plus the level of PCR product (for CMV and EBV) detected in swabs from the oropharynx, can increase in the acute phase of COVID-19.
But, from that list, it’s only CMV and EBV (plus human herpesvirus 6, HHV6) that prior to 2019 have been associated with the manifestations of the LC-like chronic fatigue syndrome (CFS).
Before the availability of antiretroviral therapy (ART) to suppress HIV replication and prevent the development of the acquired immune deficiency syndrome (AIDS), all these HVs (along with HHV9, the Kaposi’s Sarcoma virus) could potentially be reactivated in AIDS patients to cause, in some cases, lethal disease. Such HV reactivation can also happen in people who are massively immunosuppressed (with drugs or monoclonal antibodies) for cancer therapy including bone marrow reconstitution, particularly in paediatric malignancies. But when, for example, adults who are being treated for haematological cancers contract COVID-19, they are likely to die from the SARS-CoV-2 infection, not HV reactivation.
There is thus no doubt that the HVs can both be maintained ‘silently’ in our bodies and be ‘flushed from cover’ following the compromise of immune control, as a consequence of infection with another virus. But, with the millions of people to date who have survived COVID-19 there is no clear signal that the converse can happen for SARS-CoV-2 that has hypothetically managed to hide somewhere in us. As an instance, in 39 fully recovered COVID-19 patients who were then subjected to aggressive cancer chemotherapy, there was no evidence of SARS-CoV-2 reactivation.
Similarly, of the 8096 people (774 died) who are known to have been infected with the more virulent SARS-CoV-1 of 2002/3, I could find no reports of this virus reactivating in patients who were subjected to cancer chemotherapy or other immunosuppressive treatments. When examined years later (mean of 41.3 months), 233 of 369 SARS survivors who participated in a Hong Kong study were found to be still suffering from LC-like problems, especially chronic fatigue and psychiatric issues. Given that SARS was generally a more severe disease than COVID-19, this could be reflective of irreversible organ damage during the acute phase of the infection, rather than the type of LC profile that can follow an initially mild clinical experience (IMLC).
The 150+ kb HVs carry five times more genetic information than the 30kb RNA genome of SARS-CoV-2, with at least some of that HV DNA being involved in the establishment of latency and the avoidance of immune elimination. Having a large genome is, though, not essential for the persistence of DNA viruses. Some 30-40 percent of people routinely shed the tiny (5kb) JC polyomavirus (JCV) in their urine. After invasion as a gut infection, then as systemic (blood-borne) spread, JCV can establish a pattern of persistent shedding from infected kidney epithelium (uroepithelium). In HIV/AIDS, JCV can again enter the bloodstream, localize to the brain and cause the terrible white matter disease, progressive multifocal leukoencephalopathy (PML).
The retroviruses, which transmit their information from person to person as RNA, indeed have a mechanism for persisting in our bodies. These include HIV and human T cell leukemia virus type 1 (HTLV1), which can cause T cell malignancies, tropical spastic paresis and lung disease. The ‘retro’ nomenclature refers to the fact that HIV and HTLV1 virions carry a gene coding for the enzyme (a protein) reverse transcriptase (RT) that copies viral RNA to cDNA, an essential step for retrovirus replication: in that sense, these RNA viruses operate like DNA viruses! The PCR test, for example, exploits the discovery of RT (the enzyme is made in a factory) to amplify genomes for detection in the laboratory.
Additional to RT, the retroviruses code for another enzyme called integrase, which inserts HIV and HTLV1 DNA back (hence the ‘retro’) into our genomes. The consequence is that we can never really clear retroviruses from our bodies, which is one of the reasons we’ve had so little success in making HIV vaccines. Also, our genomes are ‘littered’ with bits of ‘historic’ retrovirus DNA! Maybe some clever molecular virologists will develop a ‘gene scissors’ approach to cut out these sites of retrovirus integration, but the difficulty, as with drugs and monoclonal antibodies, will be to get these molecular ‘scissors’ to the right anatomical locations.
Early on, from interactions via social media, it became obvious that some in the broader community were confused about the possibility that an RT/integrase molecular strategy could be copying SARS-CoV-2 information back to our genomes, either following infection or the administration of mRNA vaccines. But, other than the retroviruses, RNA viruses do not carry either an RT or an integrase. Transitioning to integrated DNA is pretty much impossible for SARS-CoV-2 spike mRNA (the Moderna and Pfizer vaccines) and, though it can be made to happen with added RT for viral RNA in a tissue culture dish, any persistence of a whole SARS-CoV-2 genome (as occurs with the retroviruses) inside us as integrated DNA is highly unlikely.
Next week, we’ll begin our discussion on possible mechanisms for RNA virus (other than retrovirus) persistence.