As soon as I can I will respond to your comments. In the meantime, here are some of the answers I have posted on Twitter:
“After so many years of work and as a post Epstein-Barr virus infection ME/CFS sufferer it makes me really happy that they have put our article on the cover of the August issue of Pathogens journal:
https://www.mdpi.com/2076-0817/11/8
Until recently nobody talked about post-viral syndromes (actually they should be called chronic infectious syndromes) and they left all of us patients isolated both at a health and social level.
Unfortunately it took another virus like SARSCoV2 to show us how viruses are capable of developing chronic diseases like Long COVID. It is curious that for bacterial infections we use antibiotics but for viral infections we leave it to our immune system to manage to control it. This must change. We must prevent with antiviral treatments to prevent the development of chronic diseases such as Long COVID, ME/CFS, autoimmune diseases and even cancer. It is absurd to think that everyone's immune system can resolve most viral infections. Patients who develop diseases associated with these viruses were previously completely healthy. Having one or another type of MHC-II allele can make you weaker or more resistant to certain viruses. In the case of herpesviruses, it is not the viral particles that are the problem, but the latent cells that cause the immune disruption. The Epstein-Barr virus (EBV) is one of the oldest viruses with which humans have coexisted, even since we were apes. Living with this virus has led to the evolution of its evasion mechanisms and also of our resistance mechanisms (MHC-II alleles).
In the case of EBV, the patient only needs to have one of the "ancestral" alleles (the oldest) of the MHC-II weak against EBV, since one of the main reasons why this virus is related to the MHC-II alleles is because it infects cells through the interaction of its viral protein gp42 with the cell's MHC-II. In this way it fuses its membrane with that of the cell, forming a new gp42-MHC-II complex that alters antigenic presentation to CD4 T cells, since MHC-II is essential for the immune system to know what is foreign and what is not. By decreasing this antigen presentation to CD4 T cells, an acquired immunodeficiency develops that allows any inflammatory stimulus (other infection) in any tissue to lead to the formation of EBV-infected ectopic lymphoid aggregates. This, together with the altered immunosurveillance caused by the evasion mechanisms of these cells with EBV latency (increased Th2 and Treg), would lead to increased proliferation of these cells, which would increase the risk of neoplastic transformation or autoimmune disease in these tissues.
In the case of Long COVID two things can happen. That patients have other "weak" HLA alleles against that virus or that they are the same weak alleles against EBV, allowing SarsCov2 infection to cause recruitment of B cells with EBV latency and form these lymphoid aggregates. In other words, EBV is an opportunistic virus that takes advantage of the infection of other pathogens to settle in different tissues.
These tissues finally end up with chronic inflammation by activating receptors (TLRs) that continuously detect viral genetic material, causing an increase in the inflammatory and innate response but without the adaptive response being able to control the infection completely due to the decrease in the activation of CD4 T cells. This acquired immunodeficiency also causes reactivation of other latent pathogens such as other herpesviruses and Parvovirus B19, adding more problems and more inflammation. That is why it is common to have viral reactivations in all EBV-associated diseases.
Based on the hypothesis that the problem is EBV latency cells, there are few effective treatments. If you restore cortisol levels with corticosteroids you can further immunosuppress the Th1 response and therefore further proliferation of these latency cells. If you give antivirals against EBV you prevent viral replication but you do not eliminate the latent cells. If you only give antivirals against SarsCoV 2 you do not eliminate the ectopic lymphoid aggregates with EBV latency that have formed and therefore the problem will continue. And if you try to reduce the proinflammatory cytokines with some immunomodulatory therapy, the immunodeficiency caused by the gp42/MHC-II interaction is not eliminated, so the CD4 T cells will not recognize well the cells with EBV latency I. The treatment that would be useful would be a combination of antivirals and some treatment that would make the cells with latency move to the lytic phase or move to another type of latency that is recognized by the T cells. “
“DR2-DQ6, DR3-DQ2 and DR4-DQ8 are among the oldest haplotypes in existence. These haplotypes have survived over time because they are able to recognize a greater number of antigens compared to other haplotypes, allowing them to better eliminate some pathogens. For example, individuals carrying the HLA-DR4 allele were significantly associated with greater clearance of hepatitis B virus infection. The presence of HLA-DRB1*0401 and DRB1*1501 has been associated with greater clearance of hepatitis C virus infection. And so on with other pathogens. This means that these haplotypes have survived over time and have been inherited from population to population to this day. But they have a disadvantage and that is EBV.
Since EBV is the only member of the genus Lymphocryptovirus adapted to humans, transferred to a hominid ancestor millions of years ago, it could be hypothesized that EBV immune evasion mechanisms have evolved to evade these haplotypes. Furthermore, these haplotypes have the ability to generate strong Th1 responses, releasing IFN-γ. This provides a great advantage against many pathogens but not EBV. Since IFN-γ increases MHC-II expression in cells that previously did not express it, allowing the virus to infect even more cells through gp42-MHC-II interaction. This together with the altered antigenic presentation due to gp42, causes an increase in cells with EBV latency I and 0, increasing the evasion mechanisms of these cells (increased T-reg and IL-10) that generate an increased Th2 response and therefore a greater chronification of the infection.
But why is it EBV that generates all these diseases with these resistant haplotypes against other pathogens? Because not all individuals carrying these haplotypes have developed these diseases. Only a subset have developed them, indicating that there is an environmental factor (EBV infection) that is the origin of these diseases. Especially because it is closely related to the alleles of the beta domain of HLA-II, when infecting through this pathway.
Co-infections of other pathogens in individuals carrying these haplotypes and having EBV also play a role. Any tissue infected by another pathogen increases the inflammation of this tissue by recruiting cells. with EBV latency and forming ectopic lymphoid aggregates with EBV. Autoimmune diseases may develop in these tissues. This supports the fact that the likelihood of developing Long COVID increases the more reinfections they have had with SARS-CoV2.
So treatment against these EBV latency cells would help eliminate all EBV-associated diseases.”
