The Russian woman was sick with COVID-19 for almost a year. The virus mutated 40 times, but did not kill her

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The Russian woman was sick with COVID-19 for almost a year. The virus mutated 40 times, but did not kill her
The Russian woman was sick with COVID-19 for almost a year. The virus mutated 40 times, but did not kill her

Russian scientists from the Skolkovo Institute of Science and Technology and other scientific organizations have published preliminary results of the study, which reveal in detail a record long case of coronavirus infection. "" talks about COVID-19, which lasted 318 days, as well as the causes and potential consequences of the abnormal disease.

Infection against immunity

SARS-CoV-2 is, in fact, proof of an evolutionary process: the pathogen accumulates mutations that increase the chances of transmission of the virus from person to person and contribute to the so-called evasion of the immune response. This is observed both on the scale of the human population and in the body of individual patients suffering from prolonged COVID-19, especially in those with a weakened immune system and who received monoclonal antibodies or plasma from people who have already recovered from coronavirus as therapy. Mutations facilitate the entry of the virus into the host cell or affect the binding sites of neutralizing antibodies.

Photo: Press Service of the Moscow City Hall / RIA Novosti

In addition to escaping the humoral immune response, mutant strains can also resist a cellular response. The cellular immune response involves antigen presentation, when special cells called antigen-presenting cells expose fragments of foreign molecules (antigens) on their surface for T-lymphocytes to "familiarize" with them, which then begin to attack antigen carriers, such as viral particles. The main role in this process is played by the human leukocyte antigen (HLA) or major histocompatibility complex (MHC), which binds to the antigen and forms a complex recognized by the T-lymphocyte receptors.

In the population, SARS-CoV-2 acquires changes that reduce the binding of viral antigens to HLA molecules, which weakens antigen recognition by the corresponding cytotoxic T-lymphocytes. At the same time, there is a huge variety of different HLAs, which makes it difficult for the coronavirus to evade T-cell immunity. However, with long-term COVID-19 in a single patient, the coronavirus can acquire mutations that make it less vulnerable to the T-cell immunity of that patient.

Extraordinary case

Patient C was a stage 4 non-Hodgkin B-cell lymphoma and tested positive for coronavirus in April 2020. She had close contact with patient A, who later died of pneumonia caused by COVID-19. The first negative test was received almost a year later - in March 2021. During this time, the woman suffered several serious symptoms, including fever and pneumonia. From April 30, 2020 to February 16, 2021, Patient C underwent several chemotherapy sessions using several different regimens, including rituximab based on monoclonal antibodies. On December 28, 2020, an autologous hematopoietic stem cell transplant (auto-HSCT) was performed. In January 2021, towards the end of the study period, the patient received three doses of plasma from COVID-19 recovered patients.

Researchers isolated the live virus from swab samples obtained on August 20, 2020 and February 19, 2021. Scientists followed the evolution of SARS-CoV-2 in the patient's body using genome-wide sequencing and phylogenetic analysis, which confirmed that all this time the woman suffered from one and the same infection. Scientists have confirmed that the woman did not transmit the virus to anyone else.

Evolution of coronavirus inside a patient

During the year, the virus has undergone 40 mutations, which is much faster (15, 3 to 10 minus the fourth power per year) than it happens in the population. SARS-CoV-2 has adapted to the body of one person, improving its ability to survive and reproduce faster. Several mutations affected the S-protein and were similar to those seen in other patients. Almost all the accumulated changes were found in the samples before the transfusion of donor plasma from patients who had been ill with COVID-19, which rejects the possibility of the influence of transfusion on the evolution of coronavirus. The accumulated mutations were spread across the viral genome, affecting 18 of the 26 genes of the coronavirus.

Evolution hotspot

Researchers have found an abundance of nonsynonymous mutations, that is, mutations that change one amino acid in the encoded protein to another. Eight mutations (41 percent among non-synonymous ones) occurred in the S-protein gene, which is 13 percent of the viral genome in length, and two (9 percent) affected the viral envelope gene, which makes up 0.8 percent of the genome. Many of the observed amino acid substitutions indicated positive selection in the general population, and some of them are already known to be involved in antibody escape. However, the evolution of the virus did not lead to a noticeable decrease in the sensitivity to neutralizing antibodies.

Previously, it was believed that mutations in the S-protein were fixed in response to the action of neutralizing antibodies, however, patient C did not have B-lymphocytes that produce antibodies, and she had almost no IgG antibodies. In addition, many mutations occurred in proteins that are not on the surface of the viral envelope, which can be explained by the fact that the patient still had pronounced T-cell immunity, which is able to recognize any proteins encoded in the virus genome. Thus, SARS-CoV-2 acquired a protection that allows the virus to resist only that part of the immune system that is preserved in the patient.

Photo: Press Service of AFK Sistema / RIA Novosti

The scientists confirmed that the mutations accumulated by the virus allowed it to purposely evade the presentation of antigens by alleles of the patient's major histocompatibility complex, making the T-cell immune response ineffective. Many mutations altered the amino acid composition of antigens and impaired or even prevented their presentation by HLA. These results are consistent with the hypothesis that immunocompromised patients represent a viral adaptation hotspot, causing "leaps" in the rate of SARS-CoV-2's usually uniform evolution. As the authors write in the article, such a leap could, for example, occur with the emergence of variant B.1.1.7 ("alpha"), which reached global dominance at the beginning of 2021.

Similar to antibody evasion, mutations that evade T-cell immunity acquired by a coronavirus from a single host could give rise to new epidemiologically important variants if they spread to the general population. The researchers predict that the genetic changes observed in patient C would significantly affect the immunity against SARS-CoV-2 in the general population if the improved variant was passed on.

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