HERV-W ENV antigenemia and correlation of increased anti-SARS-CoV-2 immunoglobulin levels with post-COVID-19 symptoms 2022 Oltra et al

[Andy]

Due to the wide scope and persistence of COVID-19´s pandemic, post-COVID-19 condition represents a post-viral syndrome of unprecedented dimensions. SARS-CoV-2, in line with other infectious agents, has the capacity to activate dormant human endogenous retroviral sequences ancestrally integrated in human genomes (HERVs). This activation was shown to relate to aggravated COVID-19 patient´s symptom severity. Despite our limited understanding of how HERVs are turned off upon infection clearance, or how HERVs mediate long-term effects when their transcription remains aberrantly on, the participation of these elements in neurologic disease, such as multiple sclerosis, is already settling the basis for effective therapeutic solutions. These observations support an urgent need to identify the mechanisms that lead to HERV expression with SARS-CoV-2 infection, on the one hand, and to answer whether persistent HERV expression exists in post-COVID-19 condition, on the other.

The present study shows, for the first time, that the HERV-W ENV protein can still be actively expressed long after SARS-CoV-2 infection is resolved in post-COVID-19 condition patients. Moreover, increased anti-SARS-CoV-2 immunoglobulins in post-COVID-19 condition, particularly high anti-SARS-CoV-2 immunoglobulin levels of the E isotype (IgE), seem to strongly correlate with deteriorated patient physical function (r=-0.8057, p<0.01). These results indicate that HERV-W ENV antigenemia and anti-SARS-CoV-2 IgE serology should be further studied to better characterize post-COVID-19 condition pathogenic drivers potentially differing in subsets of patients with various symptoms. They also point out that such biomarkers may serve to design therapeutic options for precision medicine in post-COVID-19 condition.

Open access, https://www.frontiersin.org/articles/10.3389/fimmu.2022.1020064/full

 

[CRG]

Another HERV-W ENV study discussed here: https://www.s4me.info/threads/clini...toms-in-long-covid-or-pasc.30509/#post-447121

 

[Hutan]

Since previous studies had evidenced increased expression of the HERV-W ENV protein in acute COVID-19 patients in association with disease severity (20, 21), this study set to determine whether the presence of this protein remains high in post-COVID-19 patients. To this end, circulating levels of HERV-W ENV protein were measured in post-COVID-19 plasma in comparison to acute COVID-19, ppHBD, and pre-pandemic CFS subjects by Simple Western technology (Figure 1). The pre-pandemic CFS group was included as an additional control group sharing clinical symptoms with post-COVID-19 condition.

Really small samples, but it's interesting. The HERV-W envelope antigens were not identified in any healthy controls. The HERV-W seems to be reactivated in some people with acute Covid-19, and a substantial proportion of people with post-Covid condition had some antigens. Most of the pre-pandemic CFS samples had no antigens, but two had relatively high levels.

I didn't see any criteria for post-Covid-19 condition other than the symptoms had continued for more than 6 months. It's described in the introduction as
"the term popularized for SARS-CoV-2 post-viral syndrome whose main persistent symptoms include sore throat, dyspnea, chronic fatigue, pain, intestinal and sleeping disturbances, cognitive deficits, anxiety and depression".

CFS was defined as compliance with CCC and/or ICC.

 

[Hutan]

HERVs are ancient retroviral DNA sequences integrated into the human genome during evolution by reaching the germline, which constitute 8% of its size (14). Despite the benefits provided by their regulatory and coding capacities (14–16), it is widely documented that aberrant HERV expression correlates with neurological disease (14, 17–19).

HERVS constitute 8% of the human genome.

From the same group:
Human Endogenous Retrovirus as Therapeutic Targets in Neurologic Disease

HERVs have occasionally provided their hosts with beneficial effects. They contribute to genomic variability, provide additional gene regulatory elements, such as alternative promoters or alternative splice sites [14,15,16,17], or rule important physiological processes. HERVs also participate in transcriptional regulation with noncoding RNAs [18,19] or in the expression of “domesticated” viral proteins. For example, an element of the HERV-W family, ERVWE1, encodes Syncytin-1, a protein essential for embryo implantation [20,21]. Additionally, some HERVs are proposed to protect the fetus by suppressing maternal immunological reactions [22,23]. Nonetheless, if uncontrolled and/or abnormally activated, HERVs can lead to detrimental effects in their host organisms by altering gene expression profiles, expressing pathogenic nucleic acids/proteins or even inducing deleterious mutations

The expression of HERVs can be controlled at different levels, but the most important are the epigenetic regulatory mechanisms [47,48] (Figure 1). While most HERVs are constitutively repressed in the human genome, some co-opted elements must become activated in a limited way, at specific time frames and in particular cell types [20,49]. To achieve this complex context-specific regulation, some HERVs harbor binding sequences for KRAB-containing zinc finger proteins (KRAB-ZFPs). Interestingly, the number of KRAB-ZFPs correlates with the LTR transposon load across species [50]. In fact, these transcriptional repressors can benefit the host via the domestication of [transposable elements], including HERVs [51].

Influenza virus has been shown to transactivate HERV-W elements by impairing the KRAB-ZFP/KAP1/SETDB1 axis, which plays an important role in controlling HERV expression, as described above (Figure 1, number 1). In vitro, influenza virus triggers loss of sumoylations on KAP1 and lowers the levels of H3K9 trimethylation and SETDB1 without affecting promoter DNA methylation status. This leads to de-repression of HERV-W elements like Syncytin-1 [130,131,132].
Besides, herpes viruses like Herpes Simplex Virus type 1 (HSV-1), Human Herpes Virus type 6 (HHV6) and Epstein-Barr Virus (EBV) are efficient at activating HERV-W elements, even on methylated promoters [113,133]. In fact, in vitro infection by HSV-1 was shown to transactivate HERV-W by stimulating LTR-directed transcription [134], inducing its expression in neuronal and brain endothelial cells [135]. Another HERV-W activator is HHV6 [27,136]. For the Epstein–Barr virus (EBV), in vitro experiments showed that the binding of the EBV major envelope protein gp350 activates the transcription of HERV-W/MSRV and Syncytin-1 in peripheral blood mononuclear cells (PBMCs) and astrocytes without requiring EBV entry [94]. Indeed, in vivo infection triggered higher MSRV activation in PBMCs when patients had or had passed symptomatic infectious mononucleosis, the clinical manifestation of EBV [137].
EBV and HHV6 not only transactivate HERV-W elements but, also, HERV-Ks [138,139,140,141,142]. Further, first-episode schizophrenia is associated with a reduction of HERV-K methylation in PBMCs [143]. However, not only viral infections have the capacity for HERV activation; cytokines can also induce their expression. HERV-K LTRs appear to be responsive to proinflammatory stimuli in ALS [144]. This opens up the intriguing possibility that the activation of HERVs in inflammatory diseases serves to create a feedback loop amplifying abnormal immune responses when pathogenic HERVs have been epigenetically de-repressed and activated. This may be readily observed when HERVs are not constitutively repressed, as it occurs with certain HERV-K copies that are accessible to cytokine-triggered signaling pathways [145] or with HERV-W elements in epigenetically primed EBV-transformed B cells

 

[Braganca]

https://www.bloomberg.com/opinion/a...-alzheimer-s-als-and-more?srnd=premium-europe

To better understand how viruses might be affecting the brain, I stopped by the National Institutes of Health to visit Avindra Nath, who is one of the few neurologists specializing in viruses — an interest he picked up after treating AIDS patients in the early 1980s. In 2014, he was the first neurologist to travel to Liberia to treat Ebola patients, and he said a fraction of those who recover suffer neurological symptoms similar to long Covid — especially chronic fatigue.

He told me that what really interests him are viruses that are embedded in our genetic codes — called endogenous retroviruses. They may have snuck in through a sexually transmitted virus that works itself into an embryo. These viruses are a source of genetic variation — and can add novel DNA to our genomes. Like mutations, these occasionally incur an advantage and spread through the population. About 8% of our genome is made of these embedded viruses.

Nath’s interest in these started when he was treating a patient who had both HIV and ALS, and after taking antiretroviral drugs, the ALS disappeared. A series of human and animal studies convinced Nath that ALS might sometimes be triggered by an embedded virus called HERV-K.

Normally HERV-K is active during fetal development, so it may have spread through the human population because it does something useful in utero. But after we’re born, it normally shuts off (due to external chemical switches that bind to DNA).

Sometimes, he told me, these “off switches” fail, and one of these embedded viruses can become reactivated. That failure might be part of the cause of ALS. After years of animal studies, he started preliminary human trialsassessing the effects of antiviral drugs on patients with ALS. He’s now planning a placebo-controlled clinical trial for drugs that he’s shown can suppress HERV-K.

He’s also studying the kinds of viruses we catch from the outside world. He thinks viruses are more likely to trigger brain diseases indirectly — not by getting directly into neurons, but by prompting inflammation. It’s the immune system’s response that causes the problem.

He’s now studying people with neurological problems following Covid infection — something that he estimates affected about 10% of people infected before vaccines were available and a much smaller fraction today. He said that at first he was very skeptical of claims that the virus hides out in the brain, but more recent studies have made him take it seriously, especially autopsy studies done by Dan Chertow at the NIH. It might be that those residual traces of the virus are causing persistent inflammation.

It’s possible that this has always been happening to some fraction of people who pick up common viruses. It’s just that it didn’t get all that much attention before the Covid pandemic. Nath said virology and neurology were two completely different worlds, and he was unique in trying to navigate both fields at the same time.