Known post-viral illnesses caused by persistent virus

As we all know viral persistence is possibly the leading hypothesis currently driving Long Covid research. There's generally two concepts on how the virus could be persisting. On the one hand via some form of viral reservoir (possibly replication competent, possibly non-cytolytic or via some other means I'm not aware of or we don't know about) or via viral PAMPS (for example persistence of antigens like the S1-protein or the N-protein).

So far only the second form has been able to be discovered in Long Covid, however it is commonly argued that persistence in the blood for multiple years of antigens, for example the spike protein or the nucleocapsid protein, are only sensible if there is some sort of viral reservoir hiding out in the tissue. Some use the existence of Post-Vac to argue that it could be different.

As such I was wondering how this comparison holds up to other post-viral diseases in which some form of a persistent virus is known to be occuring (I don't want to discuss DNA viruses here, such as possible EBV connections to various diseases, but rather want to look at the type of viral persistence that seems more likely to be occuring in Long Covid). Are there known conditions where persistence has been observed only in form of antigens?

The classical example that is usually used when discussing viral persistence in Long Covid is post-Ebola, where viral reservoirs have been found (the caveat is that these reservoirs would maybe not have been found if the virus wasn't able to infect other people via this reservoir during intercourse, something that is extremely unlikely to be the case for SARS-COV-2). To my best knowledge other examples of reservoirs include Chikungunya, West Nile virus, Hep-C and Borrelia.

Other post-viral diseases such as long-SARS (ME/CFS), long-Q-fever and post-Polio haven't been able to establish a persistent virus in any form (possibly just due to the lack of research).

I comprehend that the small sample size of conditions with known reservoirs might not be sufficient to convince someone that is certain that a possible persistence is only viral PAMPs, but are there any known conditions where antigen persistence without a reservoir is causing some havoc?

Regarding what I am writing above please take my "knowledge" with a big grain of salt, I don't know anything, I just know the names of some things, so I'd be happy if someone enlightens me.

 

I wasn't sure of the answer to your question, so I decided to ask ChatGPT.

–––––––––––

Q: Are there diseases where viral persistence has been shown to be a factor?

A: There are several diseases in which viral persistence plays a significant role. Viral persistence refers to the ability of a virus to establish long-term or chronic infections within a host, often evading the immune system and persisting for extended periods. Here are some examples of diseases where viral persistence is a factor:

1. HIV/AIDS (Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome): HIV is well-known for its ability to establish a persistent infection in the human body. It attacks the immune system, particularly CD4+ T cells, and can remain latent within these cells for an extended period, even years. This persistence can lead to the development of AIDS.
   
   
2. Hepatitis B and C: Both hepatitis B virus (HBV) and hepatitis C virus (HCV) can establish chronic infections in the liver. These chronic infections may lead to cirrhosis and liver cancer over time.
   
   
3. Herpesviruses (e.g., Herpes Simplex Virus, Epstein-Barr Virus, Cytomegalovirus): Herpesviruses are known for their ability to establish latent infections in the host, with periodic reactivation. For example, the herpes simplex virus can cause recurrent oral or genital sores, and Epstein-Barr virus is associated with mononucleosis and can lead to the development of certain cancers.
   
   
4. Human Papillomavirus (HPV): Certain high-risk types of HPV can persist and lead to the development of cervical and other cancers.
   
   
5. Varicella-Zoster Virus: This virus causes chickenpox during primary infection and can establish latency in nerve cells. Later in life, it may reactivate as shingles.
   
   
6. Human T-cell Lymphotropic Virus Type 1 (HTLV-1): This retrovirus can lead to chronic infection and is associated with diseases like adult T-cell leukemia/lymphoma.
   
   
7. Cytomegalovirus (CMV): CMV can establish lifelong latent infections, and it is a significant concern in immunocompromised individuals.
   
   
8. Measles Virus: In some cases, the measles virus can persist and lead to a condition known as subacute sclerosing panencephalitis (SSPE), which is a rare but severe neurological disorder.
   
   
9. Dengue Virus: Dengue can result in a secondary infection with a different serotype, which can be more severe due to immune-enhanced disease.
   

–––––––––––


Q: Are there diseases where viral persistence has been observed only in the form of antigens?

A: Yes, there are diseases where viral persistence is primarily observed in the form of viral antigens rather than active virus replication. In these cases, the virus may no longer be actively replicating but can leave behind viral antigens or viral genetic material in the host. This can trigger immune responses and may have implications for the health of the host. One example of such a disease is:

1. Human Papillomavirus (HPV) Infections: While HPV is primarily known for causing warts and certain cancers, some HPV types can establish latent infections and leave behind viral DNA in host cells even after the active infection has cleared. The presence of HPV DNA or viral antigens in host cells can lead to chronic immune responses and is a risk factor for the development of cervical and other cancers. Persistent HPV infections, even in the absence of active virus replication, can contribute to the progression of these diseases.

[Despite referring to diseases plural, it only suggested this one.]

 

I don't think anyone has found solid evidence of viral persistence in chikungunya, west nile (or dengue for that matter, they are all related). Borrelia is a bacteria.

 

HIV to me seems like a bad example, firstly it doesn’t seem comparable to COVID-19 and is quite a “special” virus, secondly because it usually doesn’t cause symptoms related to post-viral illnesses albeit infecting cells all over the body and thirdly because it's extremely progressive if not treated.

Measles seems somewhat relevant. Hepatitis B could definitely be added to my above list. Admittedly I had never heard of HTLV-1 before. I’m not sure about evidence of a persistent virus in Dengue albeit it being known to cause post-viral issues, perhaps you have a source (I have to acknowledge that the evidence is probably similarly weak to some of the other viruses I had mentioned)? The rest are Herpesviruses.

HPV sounds like it could be an interesting example of antigen persistence, albeit being a very different virus to COVID-19 so I can’t judge who mechanistically comparable things are. From what I know the antigens that are detected in Long Covid are usually just found haning around, without much evidence of hiding in cells (apart from the very dubious S1 persistence in monocytes research by Patterson).

Indeed, evidence of persistence of the above viruses is all rather weak, weaker than the evidence in Covid, but I can’t judge how hard this has been looked into (probably not particularly hard in vivo, but there might have been some autopsy work). Perhaps it would make sense to detail what exactly has been looked at and what has been found for these viruses.

Yes, I wasn’t sure if I should have mentioned Borrelia.