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 second most frequent recurrently 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 cell-cell transmission within the host 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.

SARS-CoV-2 evolves increased infection elicited cell death and fusion in an immunosuppressed individual

“…The day 6 isolate already evolved a considerable number of mutations, or alternatively, the infecting virus was mutated. Between day 6 and day 190 post-diagnosis, the infection evolved immune escape from neutralizing antibodies, consistent with what is observed in long-term SARS-CoV-2 infections in individuals with immunosuppression 22 . However, the ability of the virus to induce cell fusion and cell death upon infection also changed through the course of evolution.…”

“…Analysis of multiple long-term infections in immunosuppressed individuals has demonstrated recurrent mutations that are associated with escape from neutralizing antibodies 22 . However, mutations outside of spike are also common and may affect virus infection and cell-cell spread and may therefore impact pathogenicity 22 , with one possible outcome being that pathogenicity is reduced. In cell culture, viruses attenuate during long-term passaging, and such passaging is used to make live attenuated vaccines 25 .…”

Human origin ascertained for SARS-CoV-2 Omicron-like spike sequences detected in wastewater: a targeted surveillance study of a cryptic lineage in an urban sewershed

“…Together, our results indicate that a SARS-CoV-2 cryptic lineage, persistently detected in Wisconsin wastewater, was most likely derived from a single individual with prolonged infection. The mutational profile of this virus appears to bear the imprints of diversifying selection on Spike, and perhaps other gene products, consistent with reports of immunocompromised individuals with prolonged SARS-CoV-2 infections 7,8 . Our findings suggest that SARS-CoV-2 cryptic lineages in wastewater may be derived largely, or even entirely, from human, and not animal, sources.…”

“…Individuals with prolonged SARS-CoV-2 infections in the gastrointestinal tract could be a significant subgroup of unsampled infections. Individuals with immunocompromising conditions are at high risk for such prolonged infections, and suboptimal immune responses in the gastrointestinal tract of such individuals could select for antigenic variation over the course of infection 7,8 . Human waste is the predominant source of genetic material in wastewater, making it the most parsimonious explanation for the origin of SARS-CoV-2 sequences in this material.…”

Genetic diversity and evolutionary convergence of cryptic SARS- CoV-2 lineages detected via wastewater sequencing

“…In particular, substitutions at positions 417, 440, 460, 484, 493 and 501 have all been well documented to lead to immune evasion [17,27,34,[40][41][42]. Additionally, RBD changes K417T, N440K, N460K, E484A, Q493K, and N501Y have all been observed in persistent infections of immunocompromised patients [43,44]. Given the repeated appearance of these mutations in diverse sewersheds, the majority of the selective pressure on the cryptic lineages is almost certainly immune pressure.…”