Background: Chronic lymphocytic leukemia (CLL) is a B cell lymphoproliferative disorder that characteristically presents in older individuals. Small lymphocytic lymphoma (SLL) occurs when CLL cells infiltrate lymph nodes and other tissues but spare peripheral blood and bone marrow. Lymphomatoid papulosis (LyP) is an indolent cutaneous CD30+ lymphoproliferative disorder characterized by papules and nodules that develop and spontaneously regress over weeks to months. Methods: An 84-year-old man with CLL who developed LyP is described. The features of other patients who concurrently had both of these conditions are reviewed. Results: A man was diagnosed with CLL at age 50 years. At 84 years of age, he presented with red papules on his buttocks, which demonstrated a CD30+ lymphoproliferative disorder on biopsy. Correlation of the lesion history, morphology, and histopathology established the diagnosis of LyP. LyP and CLL/SLL, including in this patient, has only been reported in 11 individuals, to our knowledge. Conclusion: The concurrent expression of LyP and CLL/SLL is rare. Since the conditions derive from different lymphocyte subsets, the concurrent expression may be merely coincidental. However, the development of both conditions in the same individual may provide additional insight into the pathogenesis of these disorders.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic that is a serious global health problem. Evasion of IFN-mediated antiviral signaling is a common defense strategy that pathogenic viruses use to replicate and propagate in their host. In this study, we show that SARS-CoV-2 is able to efficiently block STAT1 and STAT2 nuclear translocation in order to impair transcriptional induction of IFN-stimulated genes (ISGs). Our results demonstrate that the viral accessory protein Orf6 exerts this anti-IFN activity. We found that SARS-CoV-2 Orf6 localizes at the nuclear pore complex (NPC) and directly interacts with Nup98-Rae1 via its C-terminal domain to impair docking of cargo-receptor (karyopherin/importin) complex and disrupt nuclear import. In addition, we show that a methionine-to-arginine substitution at residue 58 impairs Orf6 binding to the Nup98-Rae1 complex and abolishes its IFN antagonistic function. All together our data unravel a mechanism of viral antagonism in which a virus hijacks the Nup98-Rae1 complex to overcome the antiviral action of IFN.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes several proteins that inhibit host interferon responses. Among these, ORF6 antagonizes interferon signaling by disrupting nucleocytoplasmic trafficking through interactions with the nuclear pore complex components Nup98-Rae1. However, the roles and contributions of ORF6 during physiological infection remain unexplored. We assessed the role of ORF6 during infection using recombinant viruses carrying a deletion or loss-of-function (LoF) mutation in ORF6. ORF6 plays key roles in interferon antagonism and viral pathogenesis by interfering with nuclear import and specifically the translocation of IRF and STAT transcription factors. Additionally, ORF6 inhibits cellular mRNA export, resulting in the remodeling of the host cell proteome, and regulates viral protein expression. Interestingly, the ORF6:D61L mutation that emerged in the Omicron BA.2 and BA.4 variants exhibits reduced interactions with Nup98-Rae1 and consequently impairs immune evasion. Our findings highlight the role of ORF6 in antagonizing innate immunity and emphasize the importance of studying the immune evasion strategies of SARS-CoV-2.