How can viral persistence research in Long-Covid become meaningful?

How can viral persistence research in Long-Covid become meaningful?

Given that viral theories as driver for ME/CFS have existed for decades without substantial evidence being added or possible negative findings being published, it’s hard to see how such a hypothesis will start vanishing or what would be a convincing argument to completely disprove them in general as it’s hard to dissect every possible millimetre of the human body and any hypothesis without evidence surrounding “we haven’t found the correct tissue type or viral particle” seem likely to always linger around independently of whether it is valuable or likely to be true. Of course popularity phenomena surrounding certain ideas naturally die out over time if substantial evidence doesn’t arise over multiple years.

Given that it seems important to me to understand how one would go about conducting fruitful research in the viral persistence field. Similarly to other research, unfortunately, the majority of viral persistence papers appear to be neither fruitful nor useful.

The first big trends to research viral persistence in LC appears to have been initially spurred by Paxlovid results on “Paxlovid preventing LC”. Results which appear to have been heavily riddled in basic methodological flaws, so much as that most researchers completely neglect these results nowadays. Similarly initial studies such as “Persistent Presence of Spike protein and Viral RNA in the Circulation of Individuals with Post-Acute Sequelae of COVID-19” https://www.s4me.info/threads/persi...-of-covid-19-2022-craddock.29003/#post-482483 seem to not have held up the test of time, as shown in “Plasma-based antigen persistence in the post-acute phase of SARS-CoV-2 infection”. A good overview on biopsy work in regards to viral persistence of Long-Covid can be found here: www.docs.google.com/spreadsheets/d/17DcuF8wuhwRQfnYLbUrYxurF8JI41vgJujs95-5GNeI/edit, whilst reviews such as SARS-CoV-2 reservoir in post-acute sequelae of COVID-19 (PASC) have highlighted areas that need to be studied and questions that remain unanswered.

The largest problems to date appear to have been:

• vague and meaningless and differing classifications of LC lacking any meaningful description
• not having pre-pandemic and post-infection control groups
• not tying viral persistence to meaningful immunology
• not tying meaningful immunology to meaningful symptomatology

Most of the viral persistence ideas, which are typically not thought out well enough to even be called hypotheses, build around finding viral remnants and trying to somehow vaguely explain symptomatology by citing a possible immunological response to such remnants even though such an immunological response was not looked at or there is no evidence of such an immunological response.

As such key questions for me are: How much do you have to know about how and where a virus persists to study and understand possible immunological consequences? How can the knowledge about how and where a virus persists shape the immunological research you do?

It is rather clear that until now no clear immunological abnormalities have been detected, neither in ME/CFS nor in LC. So if viral persistence is driving symptomatology in a subset of patients it seems that our current understanding of immunology is either insufficient to detect what we should be looking for or that we are not looking at the right places with the right ideas and tools. In that case it seems plausible that understanding viral persistence can help us understand the immunological signals we should be looking for, but is it really necessary to know how and where a virus persists to study possible immunological responses to it, especially in illness that seem to represent symptomologies that are anything but local? Is there historical precedence that to study and understand the immunological response to viral presence it is necessary to understand viral persistence first?

With a trend towards deeper, more difficult, invasive and expensive probing of tissue to detect viral presence it remains an open question how the local presence of persistent virus or viral PAMPS could be able to cause a global multi systemic response that seemingly cannot be meaningfully studied without observing the local phenomena first. Perhaps we indeed know less about immunology than we know about viruses and this is the only way to approach such a problem.

Peluso et al’s PET study didn’t seem to be able to provide the answers many were hoping for and there currently seems to be a trend towards muscle biopsies and away from imaging studies in the viral persistence field. Whilst not a study focused in any way on viral persistence the results of Wüst et al already showed that this will be a difficult avenue of research to follow as they found viral remnants in the majority of participants independent of symptomatology and no evidence of any immunological response, making the possibility of noisy results without any causality very high. Similarly the results by Zollner et in Clearance of gut mucosal SARS-CoV-2 antigens and post-acute COVID-19 after two years in patients with inflammatory bowel disease, which was the follow-up of the previously trending paper Post-acute COVID-19 is characterized by gut viral antigen persistence in inflammatory bowel diseases, showed that any form of causality in regards to muscle biopsies and viral persistence is currently still very far away. Some other intriuing studies such as Long-Term Dysfunction of Taste Papillae in SARS-CoV-2 have not published any follow-up data yet so it is hard to evaluate how those findings fit into a larger picture.

With a tremendous amount of strong research in the viral persistence field being led by researchers with an HIV/AIDS background I wonder whether other fields of research could not be a crucial intermediate step for Long-Covid viral persistence research. Ebola persistence and Post-Ebola are commonly cited by researchers in the viral persistence field as an groundbreaking finding nobody expected. However, I cannot help but wander why none of these people has actually cared to look at viral persistence in Ebola and Post-Ebola properly, rather than using it as some handwavy argument for their own research. Since replication competent viral persistence has been proven in a subset of people following Ebola infections it seems sensible for LC research to use this field as a training ground to understand whether such viral persistence can be tied to symptomology at all in Post-Ebola and whether they can find immunogical clues by knowing details on the specific type of viral persistence that is occuring in Ebola and trying to understand whether immunology is tied to symptomolgy. Similar examples for other viruses such as Measles and Zika exist and funding will always be a problem, but to me it seems to be an too important field of research to just completely neglect apart from populistic remarks. After all a difficult scientific problem is best studied by solving a similar but less complex problem first.