Endogenous retroviruses high levels help to understand early mortality in COVID-19 patients

A study coordinated by the Oswaldo Cruz Foundation (Fiocruz) is helping to understand why some critically ill patients submitted to mechanical ventilation manage to leave the ICU, while others do not survive. The research indicates that the presence of the human endogenous retrovirus K (HERV-K) is associated not only with worsening disease but also with early mortality.

From March to December 2020, the study Human endogenous retrovirus K activation in the lower respiratory tract of severe COVID-19 patients associates with early mortality followed 25 critically ill patients who required mechanical ventilation. With an average age of 57, they were admitted to the D'Or Institute (ID'Or) and the Paulo Niemeyer State Brain Institute (IECPN, acronym in Portuguese).

The progression from mild to severe cases had been associated with hypoxia, uncontrolled inflammation, and coagulopathy. However, the mechanisms involved with mortality in very severe cases are not yet well known. To this end, the study sought to understand the tracheal aspirates virome — that is, the viruses present in the sample — from individuals on mechanical ventilation. The tests showed high levels of HERV-K, compared to the patients with mild cases and of uninfected persons.

"We checked the virome of a population with very high severity, in which the mortality rate reaches 80%, to see if some other virus was coinfecting this patient who is debilitated, immunosuppressed," says study coordinator Thiago Moreno, from the Center for Technological Development in Health (CDTS/Fiocruz). "Our surprise was to find this endogenous retrovirus K high levels. It is the kind of research that starts from a completely unbiased approach. That gives a lot of strength, a lot of credibility to the finding."

HERV-K is an endogenous retrovirus, an ancestral virus that infected the human genome when humans and chimpanzees were decoupling on the evolutionary scale. Some of these genetic elements are present in our chromosomes. Many are silent for most of our lives, but it seems that somehow SARS-CoV-2 has reactivated this ancestral retrovirus. The death rate in severe COVID-19 patients is as high as 50% among those with HERV-K high levels.

The trigger

The study also established a direct link: by infecting a healthy person's cell with SARS-CoV-2 in the laboratory, there was an increase in HERV-K levels. "We established, in fact, that SARS-CoV-2 is the trigger for the increase in these endogenous retroviruses, to awaken the silent genes," says Thiago Moreno.

Along with HERV-K increased levels in the patients, the researchers noticed that clotting factors were more consumed, more inflammatory processes occurred, and the numbers of factors necessary for the immune system cells survival decreased. As HERV-K levels increased, the activated inflamed monocytes numbers also increased.

"These HERV-K levels correlated with what was called early mortality, such as less than 28 days of hospitalization," Thiago says.

The research is still the first evidence of this retrovirus presence, in the severe COVID-19 patients' respiratory tract and plasma. The HERV-K presence — which also occurs in other diseases, such as cancer and multiple sclerosis — can be used as a biomarker associated with severity in COVID-19 cases. Its early detection could reinforce certain strategies use, such as anticoagulants and anti-inflammatory drugs, comments Thiago Moreno.

But it is still difficult to know why this occurs in some people and not in others. "This silent genes awakening is what can make the difference in evolutions. Perhaps the signal for silencing certain endogenous retroviruses is stronger in some people than in others. The new coronavirus ability to change the host cell epigenetic profile, activating even ancestral viruses, some of which should be dormant in our genome, seems to be associated with gravity", comments the study coordinator.

In addition to Thiago Moreno, Jairo Temerozo (Oswaldo Cruz Institute, IOC/Fiocruz), Natalia Fintelman-Rodrigues, Monique Cristina Santos, Carolina Sacramento, Aline Silva, Samuel Mandacaru, Emilly Caroline Moraes, Monique Trugilho, João Gesto, Marcelo Ferreira, Felipe Betoni, Remy Martins-Gonçalves, Isacláudia Azevedo-Quintanilha, Cassia Righy, Carlos Morel, Dumith Bou-Habib, Fernando Bozza and Patricia Bozza (Fiocruz); Eugênio Hottz (Federal University of Juiz de Fora); Juliana Abrantes (Federal University of Rio de Janeiro); Pedro Kurtz (Paulo Niemeyer State Brain Institute); and Hui Jiang and Hongdong Tan (MGI Tech) took part in the study.