The clinical manifestations of COVID-19 are believed to be caused by an abnormal immune response to the novel coronavirus, SARS-CoV-2. Targeting that rogue immune response is one of the approaches under investigation for treating COVID-19. Now, a team led by scientists at the University of Rome Tor Vergata has found a possible way to do just that via an otherwise silent genetic phenomenon in humans.
In a new study published by the Lancet’s EBioMedicine, the team explained the discovery of a strong correlation between the expression of the envelope protein of the human endogenous retrovirus W (HERV-W ENV) in white blood cells and markers of inflammation in COVID-19 patients.
Because HERV-W ENV has been linked to other inflammatory diseases, the researchers suggested the protein could help predict clinical progression of COVID-19 and might be targeted by drugs designed to treat the disease.
Scientists from Swiss biotech GeNeuro also participated in the study. The company is developing an anti-HERV-W antibody, temelimab, to treat multiple sclerosis. It's in phase 2 clinical testing for MS, and now the company hopes to move it into COVID-19 trials as early as this summer.
The HERV family of genes is a relic of the human genome, left from ancestral infection by retroviruses. The activation of these genes has been linked to other autoimmune diseases, including type 1 diabetes and rheumatoid arthritis. The protein HERV-W ENV can be activated by new viral infections and induces proinflammatory responses. So the University of Rome team wanted to see if it’s involved in COVID-19.
Blood cells from 30 hospitalized COVID-19 patients were compared with those from 17 healthy donors who had been matched for age and sex.
The researchers recorded significantly higher levels of HERV-W ENV mRNA and protein in lymphocytes of COVID patients. T cells with high HERV expression showed strong differentiation activity and exhaustion, which is typical of continuous immune stimulation during chronic infections.
“This pro-inflammatory protein is usually found in specific disease situations, mostly in the brain, but has never before been observed circulating in the body at high levels and, in particular, was never seen expressed in T-lymphocytes,” Claudia Matteucci, Ph.D., the corresponding author of the study, pointed out in a statement.
Further analysis showed HERV-W ENV mRNA correlated with the expression of pro-inflammatory molecules such as IL-6, IL-10 and IL-17RA. And the percentage of HERV-W ENV in lymphocytes was related to COVID-19 disease severity, as patients with high expression suffered more severe pneumonia.
In lab dishes, the researchers found that stimulating immune cells from healthy donors with the SARS-CoV-2 spike protein prompted a significant increase in early expression of HERV-W ENV. But only about 30% of healthy donor cells responded that way, scientists from GeNeuro explained in a separate study published on the preprint site Research Square. That could explain individual susceptibility to COVID-19, they suggested.
Before this study, HERVs had been observed mainly in neurologic disorders such as MS. Given the discovery of HERVs in lymphocytes, HERV-W ENV may have a double effect in COVID-19 patients, said GeNeuro Chief Scientific Officer Hervé Perron, Ph.D., a co-author of the study.
“In the short-term, when activated in genetically susceptible individuals, HERV-W ENV can act as an accelerant to the innate immune response, fueling complications and leading to the need for ventilation,” he explained in a statement. “But even after the primary infection is over, if HERV-W ENV has reached a self-fueling expression level, it may cause persistent damage to endothelial cells in blood vessels and also to cells from the peripheral and central nervous system, which could explain many of the long-term neurological symptoms experienced by patients long after SARS-CoV-2 infection.”
Based on the findings, GeNeuro is now working with medical centers in Europe and the U.S. to evaluate temelimab as a treatment both to prevent immune overreaction in acute patients and to tackle toxic neurological effects of the virus.