SARS-CoV-2 evolution during prolonged infection in immunocompromised patients

Area of Science:

• Virology
• Immunology
• Genomics

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants pose a significant threat to global health.
• Immunocompromised individuals may experience prolonged SARS-CoV-2 infections, creating environments for viral evolution.
• Understanding viral evolution pathways is crucial for developing effective treatments and control strategies.

Purpose of the Study:

• To investigate the evolutionary pathways of SARS-CoV-2 in immunocompromised patients with prolonged infections.
• To characterize the accumulation of mutations and identify specific variants that emerge during long-term viral persistence.
• To assess the impact of host immune status and therapeutic interventions on viral evolution.

Main Methods:

• Analysis of viral genome sequences from five immunocompromised patients with prolonged SARS-CoV-2 infection (79-203 days).
• Generation of at least two independent viral genome sequences per timepoint to ensure accuracy and assess heterogeneity.
• Monitoring of mutation rates and identification of specific substitutions in the viral genome, particularly in the spike protein.

Main Results:

• Prolonged SARS-CoV-2 infection in immunocompromised patients led to higher rates of viral genome substitution accumulation compared to community background.
• The spike protein coding region showed a significantly higher density of unique mutations.
• Emergence of SARS-CoV-2 variants with substitutions conferring resistance to monoclonal antibodies (bebtelovimab and sotrovimab) was observed.
• No remdesivir-resistant substitutions were detected despite patient treatment.

Conclusions:

• Long-term SARS-CoV-2 infection in immunocompromised individuals is a significant driver of viral evolution and variant generation.
• The spike protein is a key target for viral adaptation, leading to immune escape mechanisms.
• Monitoring viral evolution in persistent infections is essential for understanding pandemic dynamics and guiding therapeutic strategies.