Biology subjects

Hisner, R.

Publications and source records attributed to Hisner, R..

5 recordsLinked to original sources

bioRxiv2026

Coevolving Mutations in Chronic SARS-CoV-2 Infections

The SARS-CoV-2 pandemic has been marked by two outstanding features that have had major impacts on global public health: the repeated emergence and growth of highly divergent saltation variants with no known close relatives and the development of adverse health effects extending beyond the period of acute infection, called long Covid, in a proportion of the population. Chronic infections in immunocompromised hosts are the most likely explanation for the emergence of saltation variants, and some evidence indicates that viral persistence contributes to long Covid. Knowledge of intrahost evolution during prolonged SARS-CoV-2 infection is therefore vital for understanding the global evolution of SARS-CoV-2 and for deciphering the nature of long Covid and promising avenues for treatment. We assembled a collection of over 3000 independent, full-length SARS-CoV-2 sequences deriving from posited or confirmed chronic infections. We describe 14 distinct mutation patterns (MPs) that repeatedly appear in these sequences--each involving mutations in multiple genomic regions--including four CD8 T cell-escape MPs and two MPs that represent adaptation to tissue compartments outside the upper-respiratory tract. The existence of these MPs promises new insights into the life cycle and evolution of SARS-CoV-2 and the nature of persistent SARS-CoV-2 infection.

evolutionary biology↗

bioRxiv2026

SARS-CoV-2 saltational events are recurrent and trace to persistent human infections

SARS-CoV-2 evolution is characterized by gradual mutation accumulation but has been punctuated by rare yet impactful highly mutated variants. Whether such saltational jumps are a broad feature of SARS-CoV-2 evolution or rare anomalies remains unclear. We systematically investigate SARS-CoV-2 saltational evolution by developing a scalable framework to detect saltational events from 4.4 million high-quality viral genomes. Saltational events occurred at low but detectable rates during the pandemic and post-pandemic periods and across geographies. Their mutational signature closely matches that seen in persistent human infections but is inconsistent with the signatures of mink or deer infections. This points to persistent infection, rather than reverse zoonosis, as their primary source. While most saltational events lack evidence of onward transmission, those that do tend to carry mutations found in successful clades. Our work demonstrates that the emergence of highly mutated SARS-CoV-2 variants reflects a recurrent evolutionary process, with implications for preparedness.

evolutionary biology↗

bioRxiv2026

SARS-CoV-2 BA.3.2.2 is more evasive of neutralization by sera from young children

Dominant SARS-CoV-2 variants have most prominently displayed greater evasion of serum neutralizing antibodies than predecessor strains. BA.3.2, a descendant of Omicron BA.3, carrying 43 additional spike mutations, emerged in 2024, and over the last several months its subvariant BA.3.2.2 has slowly increased in prevalence globally. BA.3.2.2 continues to circulate at lower frequency than the genetically and antigenically distant dominant JN.1 subvariants NB.1.8.1 and XFG. However, concerningly, epidemiologic analyses have suggested that a larger proportion of COVID-19 cases in children are caused by BA.3.2.2 compared to adults, raising the possibility that susceptibility to BA.3.2.2 differs across age groups. Since immune imprinting shapes variant-specific anti-SARS-CoV-2 antibody profiles and children born after 2021 primarily were first exposed to Omicron subvariants, we hypothesized that young children may have lower circulating neutralizing antibody titers against BA.3.2.2 than adults. Using pseudovirus neutralization assays, we measured titers against BA.3.2.2 and other SARS-CoV-2 variants in serum or plasma samples from a total of 36 adults ([≥]18 years old), school-age children (3-10 years old), and infants/toddlers (6-28 months old) in the US. We found that both cohorts of children had lower geometric mean titers against BA.3.2.2 than adults, even though all tested age groups had similar titers against dominant strains NB.1.8.1 and XFG. Together, these findings suggest that susceptibility to emerging SARS-CoV-2 variants may diverge across age groups, perhaps as a result of their different exposure histories. Furthermore, these results highlight the importance of SARS-CoV-2 surveillance and the monitoring of immunity against viral variants across age ranges.

microbiology↗

bioRxiv2026

The conserved QTQTX motif in the SARS-CoV-2 spike protein is dispensable for cleavage and lung cell entry of the emerging variant BA.3.2

The furin motif in the SARS-CoV-2 spike (S) protein is important for lung cell entry. It is embedded in an extended loop structure and preceded by a highly conserved QTQTX motif that is required for efficient furin cleavage of the SARS-CoV-2 WA-1 S protein. BA.3.2 is an emerging SARS-CoV-2 saltation variant that is spreading globally in April 2026 and encodes for a highly mutated S protein. Here, we analyzed whether the QTQTX motif is also required for spike protein cleavage and lung cell entry of BA.3.2. We report that two patient-derived spike sequences of the BA.3.2 subvariant BA.3.2.2 lack the first QT repeat of the QTQTX motif and show that this motif is largely dispensable for both cleavage and lung cell entry of BA.3.2.2, which we found to depend on TMPRSS2. Our results suggest that the reconfiguration of the BA.3.2 S protein during persistent infection may have significantly altered the determinants of furin cleavage. IMPORTANCEThe furin motif in the SARS-CoV-2 spike (S) protein is unique among sarbecoviruses and constitutes a virulence determinant. A QTQTX motif located immediately upstream of the furin motif is required for furin cleavage of the S protein of the virus that circulated early in the pandemic. Here, we show that the QTQTX motif is largely dispensable for S protein processing and S protein-driven lung cell entry of the emerging saltation variant BA.3.2, which is currently spreading globally. Thus, BA.3.2 evolution within immunocompromised individuals may have relaxed the requirements for furin processing of the spike protein.

microbiology↗

bioRxiv2026

Genetic Evidence Indicates the Evolutionary Importance of the SARS-CoV-2 ORF9b protein

All known betacoronaviruses possess an overlapping alternate-frame gene within the nucleocapsid gene. In SARS-CoV-2, the gene for this "internal protein" is ORF9b. The WHO Variants of Concern (VOC) Alpha, Delta, and Omicron all possess noncoding mutations that increase ORF9b expression. We show that with two exceptions, every major variant of the VOC era has had similar noncoding mutations to increase ORF9b expression and that these mutations are also frequently seen in long-branch, anachronistic, posited chronic-infection (PCI) sequences. Furthermore, we show that the amino acid substitution rate in ORF9b is higher than for any other SARS-CoV-2 gene, both in high-quality circulating sequences and in PCI sequences. This suggests that, as immunity to SARS-CoV-2 has grown in the population, increased ORF9b expression has conferred an evolutionary advantage, likely due to its ability to antagonize the antiviral type-I interferon response. We also show that PCI sequences are marked by distinct mutational patterns in ORF9b, some of which later became prominent in major variants. This evidence points to the importance of ORF9b for both viral transmission and within-host persistence.

microbiology↗