Viral persistence, reactivation, and mechanisms of long COVID, 2023, Chen et al.

[SNT Gatchaman]

Viral persistence, reactivation, and mechanisms of long COVID
Benjamin Chen; Boris Julg; Sindhu Mohandas; Steven B Bradfute; RECOVER Mechanistic Pathways Task Force; Zaki A Sherif; Christian R Gomez; Thomas J Connors; Timothy J Henrich; W Brian Reeves; K Coombs; C Kim; Pras Jagannathan; Christian Bime; Erin Burke Quinlan; Michael A Portman; Maria Laura Gennaro; Jalees Rehman

The COVID-19 global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has infected hundreds of millions of individuals. Following COVID-19 infection, a subset can develop a wide range of chronic symptoms affecting diverse organ systems referred to as post-acute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID.

A National Institutes of Health-sponsored initiative, RECOVER: Researching COVID to Enhance Recovery, has sought to understand the basis of long COVID in a large cohort. Given the range of symptoms that occur in long COVID, the mechanisms that may underlie these diverse symptoms may also be diverse.

In this review, we focus on the emerging literature supporting the role(s) that viral persistence or reactivation of viruses may play in PASC. Persistence of SARS-CoV-2 RNA or antigens is reported in some organs, yet the mechanism by which they do so and how they may be associated with pathogenic immune responses is unclear. Understanding the mechanisms of persistence of RNA, antigen or other reactivated viruses and how they may relate to specific inflammatory responses that drive symptoms of PASC may provide a rationale for treatment.

Link (eLife)

 

[SNT Gatchaman]

An intriguing aspect of PASC is the discovery of reactivation of latent viruses after SARS-CoV-2 infection. It has been shown that EBV, a herpesvirus that infects a majority of individuals and is typically in a latent state, can be reactivated after SARS-CoV-2 infection. Some studies have demonstrated a correlation between EBV reactivation and development of PASC. There has been evidence of reactivation of other herpesviruses, including cytomegalovirus, herpes simplex virus 1, human herpesvirus 6, and human herpesvirus 7, in acute SARS-CoV-2 infection, although the association with these viruses and development of PASC has not been ascertained. Furthermore, some human endogenous retroviruses (HERVs) have been associated with more severe acute SARS-CoV-2 infection.

Therefore, while a few herpesviruses are known to be reactivated in PASC and other viruses have been found to be upregulated in acute disease, identification of the full range of viral species or nonviral pathogens that can be reactivated or triggered has not been characterized. Performing plasma DNA PCR screening or RNA sequencing in samples from people with PASC should answer the question of which latent pathogens are reactivated in PASC versus non-PASC convalescent individuals. Specifically, what spectrum of viruses is reactivated in PASC? Also of interest is whether the timing of latent virus reactivation relative to symptomatic onset of PASC is relevant.

For DNA, only if they are reactivated fully to the lytic state, where viral DNA might then be present extra-cellularly and therefore detectable in plasma? From HHV-6 encoded small non-coding RNAs define an intermediate and early stage in viral reactivation (2018) —

we identified an early stage of viral reactivation, which we define as transactivation that is marked by transcription of several viral small non-coding RNAs (sncRNAs) in the absence of detectable increase in viral replication and proteome

(MicroRNAs aka miRNA are a subset of small non-coding RNAs aka sncRNA. Transactivation is also termed abortive-lytic.) Unclear how easily they might be detectable in blood via RNA sequencing, as above, rather than viral DNA.

From the case report included in the 2018 paper —

No viral DNA was detected in post-mortem kidney, skin biopsies except for post-mortem liver biopsy where log20 fold HHV-6A DNA was detected in the absence of HHV-6B. In contrast, HHV-6 sncRNA-U14 was detected in liver, myocardium, kidney, and coronary artery biopsies by FISH analysis. We then traced back the biopsy samples collected during the mid-stage (second hospitalization) of the disease. FFPE-biopsies taken from skin at the very beginning of the disease, clot, kidney and liver were positive for HHV-6 sncRNA-U14. These results point towards potential use of HHV-6 sncRNA-U14 as a biomarker for early detection of viral activation in clinical materials.