what virologists still don’t know

SARS-CoV-2 conquered the planet in early 2020, causing the covid-19 pandemic. How much progress has been made in understanding this virus?

Before the start of the epidemic, there were no serological tests for coronaviruses. We did not have a vaccine or treatment. We hardly knew how to care for patients. In one year, specific RT-PCR diagnostic tools for SARS-CoV-2 have been developed, serological tests have been developed and we already have several vaccines. These advances, which should allow the control of the pandemic, have been obtained very soon, although it has seemed a long time.

It is true that there is still no specific treatment for SARS-CoV-2, but we have learned a lot – and quickly – about the clinical aspects. The way patients are treated has evolved dramatically compared to the procedures of a year ago, when the disease was less known. Now we know when to use corticosteroids such as dexamethasone, how to assist critically ill patients with less aggressive treatments than in the first days, etc. In fact, the number of deaths has been reduced.

On the other hand, the advance in the knowledge of the virus itself has been less, as well as the way in which it interacts with the immune system …

That’s how it is. The answers will come little by little, in a year, two years … This type of research requires a lot of time, since it concerns fundamental virology.

First, It is necessary to be able to reproduce the multiplication of SARS-CoV-2 in the laboratory using cell cultures. We already had the tools for this, but they had to be adapted to this new coronavirus, which takes time. Once these methods are ready, the different specialists can begin to carry out their investigations: immunologists will try to identify the pathways of the immune system that the virus activates or inactivates, virologists will produce modified viral proteins in order to study its interaction with different cellular components such as the ECA2 receptor, the “lock” that SARS-CoV-2 uses to open a path that allows it to enter cells …

As soon as the first data is obtained, it must be validated, compared with data from other research groups … There are certain studies that have already generated results. For example, the spicule protein – present in many specimens on the surface of the virus – was immediately characterized, which interacts with the ECA2 cellular receptor and allows SARS-CoV-2 to penetrate cells. Why? Because we knew from our experience with other viruses that it is the protein that causes the strongest reactions of the immune system, so it is important for the development of vaccines. In order to investigate this mechanism, it was essential to know certain characteristics of this protein.

Which are the next steps?

The most interesting results will come from the characterization of the viral enzymes: the polymerase and the proteases of the virus. The first allows it to copy its genetic material, an essential stage for its multiplication within infected cells. The latter act as “scissors” that fragment the proteins that make these cells produce, proteins such as those that make up their capsid (the envelope that protects the genetic material of the virus). This other stage is essential to make them usable.

Polymerase and protease are very important targets for antiviral drugs. HIV treatments contain protease and reverse transcriptase (name for HIV polymerase) inhibitors. To get effective antivirals, it is important to know these enzymes thoroughly. To begin with, you have to be able to understand their three-dimensional structure so that chemists who are involved in drug design can create molecules that “stick” to the important parts of these enzymes and prevent them from acting. It is not easy, since its study requires the production of large quantities of these enzymes and with a very high degree of purity (in order not to disturb the precision of the analyzes that will be carried out later).

Another expected result is that of research on “universal vaccines”. The idea would be to develop vaccines that trigger the production of broad spectrum neutralizing antibodies (or bNAb, broadly neutralizing antibodies). These antibodies would attack protein motifs conserved on the surface of related viruses, making them effective against the various variants in circulation. Studies have been going on for several years, especially for HIV.

It is also true that specialists in viral epidemiology hope that variants more adapted to the human being will emerge. Indeed, we know that when a virus infects a new host, although it takes a certain time to adapt to it, it ends up doing so, but in the process it also loses some of its virulence. These mechanisms are well understood by the influenza virus: within a year or two, the viruses responsible for influenza pandemics fade into epidemic influenza viruses that return every winter.

At the moment, no such attenuation has been observed in the coronavirus. It is not that it is something unexpected since, unlike the flu virus, coronaviruses have a mechanism that corrects the errors that may appear when they copy their genetic material. In short, they evolve more slowly. The appearance of variants has been notably longer than in the case of influenza. In this case, it is the first time that we have attended this process, so we do not know how long it takes.

The origins of the virus remain to be elucidated, is not it?

Certain. Although we are certain that the origin of the virus is in the bat, we still do not know which was the intermediate host (or intermediate hosts) that have allowed it to pass from that animal to the human being. At first the pangolin was considered, but in the end it has been confirmed that this hypothesis is unlikely.

The identification of the intermediate hosts is important, as it allows us to understand the mechanisms that have made the appearance of the virus in humans possible and, therefore, to propose measures to prevent its recurrence. These are very long investigations, which require the mobilization of naturalists capable of identifying the Asian species that may have been involved, collecting samples of the wild fauna, analyzing them, etc. And that also takes a lot of time.