Serial sequencing of the SARS-CoV-2 genome in immunosuppressed patients receiving antiviral treatments and/or antibodies suggests that high viral load in these hosts allows for a rapid emergence of new treatment-resistant variants. For instance, all available data suggests that the Omicron variant developed in an immunocompromised patient.
We sought to identify SARS-CoV-2 virus mutations resulting from intrahost evolution in patients with pre-existing conditions that compromise immunity, e.g., patients who had been undergoing treatments for HIV, cancer, or organ transplants when they were infected with SARS-CoV-2.
We conducted a literature review to identify 44 immunocompromised patients with prolonged SARS-CoV-2. We then retrieved all the SARS-CoV-2 gene sequences that emerged throughout each patient’s course of treatment for SARS-CoV-2. We annotated the amino acid changes seen across the SARS-CoV-2 genome in the samples taken from the patients. These annotations were computed and modeled to predict changes in the SARS-CoV-2 genome that are likely to arise in immunocompromised patients.
As expected, we identified several mutations in the Spike protein and the viral RNA-dependent RNA polymerase (RdRp) likely selected by the antiviral treatments. Surprisingly, among all the tracked mutations in the SARS-CoV-2 genome in the studied immunocompromised patients, recurrent mutations were found at a unique position in the Envelope protein. In fact, out of 44 examined patients, 9 of them had the amino acid substitution T to I at position 30 (T30I). The Envelope protein is involved in several aspects of the virus’ life cycle. More recently, it has been shown to alter the host’s innate immune response to SARS-CoV-2, making it a protein of interest in further studies.
Significance and questions for further research
Our findings are a preliminary step in developing personalized SARS-CoV-2 treatments for immunocompromised patients, the capacity to predict the potential risk posed by new variants, and vaccines for new variants.
Further research could build on our results and contribute to these goals by investigating the functional impacts of mutations in the Envelope Protein. For instance, how do these changes in the SARS-CoV-2 genome affect pathogenesis? Do they play a role in the emergence of SARS-CoV-2 variants of interest and variants of concern? How do these mutations contribute to high viral load and severe symptoms?