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Long-term COVID-19 Infections and Virus Mutations

Study reveals insights into SARS-CoV-2 mutations during prolonged infections.

Natalie Rutsinsky, Adi Ben Zvi, Ido Fabian, Shir T. Segev, Bar Jacobi, Sheri Harari, Suzy Meijers, Yael Paran, Adi Stern

― 6 min read


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COVID-19 threw the world a major curveball, and the virus that causes it, SARS-CoV-2, has had some interesting siblings since it started spreading. As it moved from person to person, new versions of the virus popped up. Some of these new versions are like the virus had a makeover, making them more contagious than the originals. The World Health Organization got involved and labeled these new versions as Variants of Concern, because they could be more dangerous to public health.

What’s the Deal with These Variants?

Scientists think that some of these new versions may come from people who have been infected for a long time—sometimes over 21 days! When someone has a chronic infection, the virus can stick around and change over time. These long-lasting infections are often seen in people with weakened Immune Systems, such as those fighting cancer or living with conditions like AIDS. But don’t worry too much! Chronic Infections are still pretty rare among the general population.

Interestingly, a recent study found that some people without major health issues might also have prolonged infections, but this is quite rare. Even with these cases, researchers found that most of these chronic infections don’t seem to spread the virus further. However, the worry remains that if enough cases exist globally, one of these variants could potentially be contagious.

The Mystery of Rapid Changes

There’s a lot of buzz about how quickly the virus can change in these long-term infections. Some studies have highlighted that rapid changes can happen, but it’s still unclear if that’s the norm or just a rare occurrence. It might be that the virus is under significant pressure to change, or it might just be that it’s mutating faster in these patients. To really figure this out, researchers need to look closely at how different versions of the virus are behaving over time. However, studying these changes is not easy. When looking at samples from people who are sick, researchers often deal with high error rates in the tests, making it tough to get accurate results.

To improve accuracy, researchers often take extra precautions, like verifying mutations in samples more than once or focusing on mutations that occur frequently. Still, using these methods can lead to losing some important information, especially about rare mutations.

Our Study

In this study, we looked at a group of nine patients who were infected with SARS-CoV-2 for an extended period. We aimed to gather reliable genetic data from their samples. By sequencing each sample more than once, we significantly improved the accuracy of our findings. This allowed us to see how the virus mutated over time in these patients, leading to some fascinating observations.

The Mutation Rollercoaster

At first, we checked how many mutations occurred at different spots in the virus's genetic makeup. We found that at low mutation frequencies, the distribution was even. However, for higher frequencies, mutations appeared more frequently at one specific position. This suggested that those mutations were relevant and not random errors from the sequencing process.

When we examined the genetic diversity of samples from both chronic and acute infections, we found that chronic infections generally exhibited significantly more diversity. The longer the infection lasted, the more chances the virus had to change.

A Closer Look at Patients

Next, we took a closer look at each patient. Despite some patients being infected for a longer time, the amount of change in the virus was very different among them. For instance, one patient didn't show any significant mutation even after 35 days, while another had many changes in a shorter period.

One of the patients we studied had an extended infection lasting 241 days. For the first part of their infection, not much changed, but as time went on, we noticed several mutations popping up in their virus. Many of these variations could lead to changes in how the virus behaves and possibly its transmissibility.

Understanding Synonymous and Non-synonymous Mutations

The mutations we tracked could be divided into two categories: synonymous and non-synonymous. Synonymous mutations are like harmless alterations that don't change how proteins work. Non-synonymous mutations, on the other hand, can change how the virus interacts with the body’s immune system.

We found that the rate of synonymous mutations across all patients matched previous estimates of the viral mutation rate from other studies. However, non-synonymous mutation rates varied a lot! This suggests that while some patients saw dramatic changes in the virus, others didn’t experience much evolution.

The Mystery of Defective Viruses

Some mutations we tracked were found in low frequencies and didn't seem to help the virus at all. In one particular patient, we noticed lots of mutations that appear to be "defective." This means that those mutations might not help the virus survive or spread. It could be that this patient had multiple viruses infecting them simultaneously, which led to these low-quality mutations hanging around.

In sharp contrast, there was another patient who had notable mutations that helped the virus avoid the immune system. These changes were linked to the virus's ability to survive and adapt during the infection.

What Do We Learn from All This?

From our study, we gathered several important insights about SARS-CoV-2. First, we found that while chronic infections can lead to significant mutations, such cases are still quite rare. The small number of patients in our study means that we can’t assume this applies to everyone with prolonged infections.

Interestingly, the mutation patterns we observed suggest that not all chronic infections are the same. Factors like the patient’s overall health, their immune response, and the treatments they received played a big role in how quickly the virus changed. Some patients had very little evolution, while others showed many changes that could lead to new variants.

The Bottom Line

The emergence of new SARS-CoV-2 variants may often depend on these rare instances of long-term infections. The more we understand these processes, the better we can prepare for any future challenges that might arise from these variants.

The journey of studying these viruses has just begun, and while we still have many questions, the answers will help shape our response to COVID-19 and its ongoing challenges. Plus, it’s a reminder of just how tricky these little viruses can be! So, while we’re all trying to keep the virus at bay, it’s also a good idea to keep an eye on what it’s up to—because you never know when it might pull a fast one on us again!

Original Source

Title: Diverse patterns of intra-host genetic diversity in chronically infected SARS-CoV-2 patients

Abstract: In rare individuals with a severely immunocompromised system, chronic infections of SARS-CoV-2 may develop, where the virus replicates in the body for months. Sequencing of some chronic infections has uncovered dramatic adaptive evolution and fixation of mutations reminiscent of lineage-defining mutations of variants of concern (VOCs). This has led to the prevailing hypothesis that VOCs emerged from chronic infections. To examine the mutation dynamics and intra-host genomic diversity of SARS-CoV-2 during chronic infections, we focused on a cohort of nine immunocompromised individuals with chronic infections and performed longitudinal sequencing of viral genomes. We show that sequencing errors may cause erroneous inference of high genetic diversity, and to overcome this we used duplicate sequencing across patients and time-points, allowing us to distinguish errors from low frequency mutations. We further find recurrent low frequency mutations that we flag as most likely sequencing errors. This stringent approach allowed us to reliably infer low frequency mutations and their dynamics across time. We inferred a synonymous divergence rate of the virus of [~]2x10-6 mutations/base/day, consistent with the SARS-CoV-2 mutation rate estimated in tissue culture. The rate of non-synonymous divergence varied widely among the different patients. We highlight two patients with opposing patterns: in one patient the rate of divergence was zero, yet this patient harbored multiple presumably defective viruses at low frequencies throughout the infection. Another patient exhibited dramatic adaptive evolution, including clonal competition. Overall, our results suggest that the emergence of highly divergent variants from chronic infections is likely a very rare event and this emphasizes the need to better understand the conditions that allow such emergence events.

Authors: Natalie Rutsinsky, Adi Ben Zvi, Ido Fabian, Shir T. Segev, Bar Jacobi, Sheri Harari, Suzy Meijers, Yael Paran, Adi Stern

Last Update: 2024-12-16 00:00:00

Language: English

Source URL: https://www.biorxiv.org/content/10.1101/2024.11.23.624482

Source PDF: https://www.biorxiv.org/content/10.1101/2024.11.23.624482.full.pdf

Licence: https://creativecommons.org/licenses/by-nc/4.0/

Changes: This summary was created with assistance from AI and may have inaccuracies. For accurate information, please refer to the original source documents linked here.

Thank you to biorxiv for use of its open access interoperability.

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