Recurrent SARS-CoV-2 Mutations in Immunodeficient Patients

Abstract

Long-term SARS-CoV-2 infections in immunodeficient patients are an important source of variation for the virus but are understudied. Many case studies have been published which describe one or a small number of long-term infected individuals but no study has combined these sequences into a cohesive dataset. This work aims to rectify this and study the genomics of this patient group through a combination of literature searches as well as identifying new case series directly from the COG-UK dataset. The spike gene receptor binding domain (RBD) and N-terminal domains (NTD) were identified as mutation hotspots. Numerous mutations associated with variants of concern were observed to emerge recurrently. Additionally a mutation in the envelope gene, - T30I was determined to be the most recurrent frequently occurring mutation arising in persistent infections. A high proportion of recurrent mutations in immunodeficient individuals are associated with ACE2 affinity, immune escape, or viral packaging optimisation. There is an apparent selective pressure for mutations which aid intra-host transmission or persistence which are often different to mutations which aid inter-host transmission, although the fact that multiple recurrent de novo mutations are considered defining for variants of concern strongly indicates that this potential source of novel variants should not be discounted.

A comparison of four epidemic waves of COVID-19 in Malawi; an observational cohort study

“…This is consistent with other studies in sub-Saharan Africa where patients admitted with COVID-19 during Omicron waves had comparatively less severe disease [ 16 , 27 , 28 ]. There is a high burden of HIV and a low SARS-CoV-2 vaccine coverage in Malawi [ 29 ], this provides a plausible environment for the emergence of novel VOCs [ 30 – 33 ]. It is crucial to identify potential VOCs rapidly and report these internationally.…”

Selection Analysis Identifies Clusters of Unusual Mutational Changes in Omicron Lineage BA.1 That Likely Impact Spike Function

“…Accordingly, S/Q493R (as occurs in BA.1) escapes some class 2 neutralizing antibodies ( Liu et al 2022 ), and S/Q493R and S/Q493K escape mutations have been selected in VSV in vitro experiments ( Weisblum et al 2020 ). S/Q493K, S/G496S, S/Q498R, and S/Y505H mutations have also all arisen previously in the context of chronic SARS-CoV-2 infections ( Choi et al 2020 ; Maponga et al 2022 ; Riddell et al 2022 ; Wilkinson et al 2022 ). The S/Q498R and S/Q493R mutations yield two additional salt bridges when binding human ACE2 ( Mannar et al 2022 ; McCallum et al 2022 ) and it is likely that the increased affinity of BA.1 Spike for human ACE2 relative to that of Alpha, Beta, Delta, and Wuhan-Hu-1 ( Cameroni et al 2022 ; Meng et al 2022 ; Peacock et al 2022 ) will further decrease its sensitivity to neutralization.…”

Investigating the evolutionary origins of the first three SARS-CoV-2 variants of concern

“…Several studies have now shown evidence of recurrent SARS-CoV-2 mutations in immunocompromised patients [15–17], with some suggesting the detection of a variant-like lineage which arose from a chronic infection that spilled over into a local population [43]. Another major implication of our work is that we can now quantitatively explain the possibility of such events and find the expected time that it takes for a new VOC to emerge from a within-host evolutionary pathway that involves any number of mutations.…”