Intra-host viral populations of SARS-CoV-2 in immunosuppressed patients with hematologic cancers

Abstract

Throughout the SARS-CoV-2 pandemic, several variants of concern (VOC) have been identified, many of which share recurrent mutations in the spike protein's receptor binding domain (RBD). This region coincides with known epitopes and can therefore have an impact on immune escape. Protracted infections in immunosuppressed patients have been hypothesized to lead to an enrichment of such mutations and therefore drive evolution towards VOCs. Here, we show that immunosuppressed patients with hematologic cancers develop distinct populations with immune escape mutations throughout the course of their infection. Notably, by investigating the co-occurrence of substitutions on individual sequencing reads in the RBD, we found quasispecies harboring mutations that confer resistance to known monoclonal antibodies (mAbs) such as S:E484K and S:E484A. Furthermore, we provide the first evidence for a viral reservoir based on intra-host phylogenetics. Our results on viral reservoirs can shed light on protracted infections interspersed with periods where the virus is undetectable as well as an alternative explanation for some long-COVID cases. Our findings also highlight that protracted infections should be treated with combination therapies rather than by a single mAbs to clear pre-existing resistant mutations.

Integrating Machine Learning-Enhanced Immunopeptidomics and SARS-CoV-2 Population-Scale Analyses Unveils Novel Antigenic Features for Next-Generation COVID-19 Vaccines

“…To achieve this, we built and interrogated our intra-host database composed of thousands of SARS-CoV-2 sequences that were isolated and sequenced directly from infected individuals. Such databases have indeed proven to be increasingly powerful to track intra-host variation and evolutionary dynamics of SARS-CoV-2 populations in COVID-19 patients [68][69][70]107 . Interestingly, we did not find the exact same deletion as observed in vitro, but we did observe a large number of deletions of various lengths (1 to 100 nucleic acid) in several regions of S leading to altered reading frames.…”