Search

We investigate JN.1-derived subvariants SLip, FLiRT, and KP.2 for neutralization by antibodies in vaccinated individuals, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients, or class III monoclonal antibody S309. Compared to JN.1, SLip, KP.2, and especially FLiRT exhibit increased resistance to bivalent-vaccinated and BA.2.86/JN.1-wave convalescent human sera. XBB.1.5 monovalent-vaccinated hamster sera robustly neutralize FLiRT and KP.2 but have reduced efficiency for SLip. All subvariants are resistant to S309 and show decreased infectivity, cell-cell fusion, and spike processing relative to JN.1. Modeling reveals that L455S and F456L in SLip reduce spike binding for ACE2, while R346T in FLiRT and KP.2 strengthens it. These three mutations, alongside D339H, alter key epitopes in spike, likely explaining the reduced sensitivity of these subvariants to neutralization. Our findings highlight the increased neutralization resistance of JN.1 subvariants and suggest that future vaccine formulations should consider the JN.1 spike as an immunogen, although the current XBB.1.5 monovalent vaccine could still offer adequate protection. [Display omitted] • SLip, FLiRT, and KP.2 are poorly neutralized by bivalent-vaccinated sera • XBB.1.5-vaccinated hamster and JN.1 patient sera neutralized SLip, FLiRT, and KP.2 • S mutations R346T, L455S, and F456L alter ACE2 binding and neutralization epitopes • SLip, FLiRT, and KP.2 spikes exhibit less fusion and processing relative to JN.1 Li et al. show that JN.1 subvariants SLip, FLiRT, and KP.2 are poorly neutralized by bivalent vaccinee sera and completely resistant to mAb S309. Sera of XBB.1.5-vaccinated hamsters and people infected by JN.1 better neutralized the variants, though to a lesser extent compared to JN.1. All subvariants exhibited reduced fusion. [ABSTRACT FROM AUTHOR]

Combination therapy (lenvatinib/programmed death-1 inhibitor) is effective for treating unresectable hepatocellular carcinoma (uHCC). We reveal that responders have better overall and progression-free survival, as well as high tumor mutation burden and special somatic variants. We analyze the proteome and metabolome of 82 plasma samples from patients with hepatocellular carcinoma (HCC; n = 51) and normal controls (n = 15), revealing that individual differences outweigh treatment differences. Responders exhibit enhanced activity in the alternative/lectin complement pathway and higher levels of lysophosphatidylcholines (LysoPCs), predicting a favorable prognosis. Non-responders are enriched for immunoglobulins, predicting worse outcomes. Compared to normal controls, HCC plasma proteins show acute inflammatory response and platelet activation, while LysoPCs decrease. Combination therapy increases LysoPCs/phosphocholines in responders. Logistic regression/random forest models using metabolomic features achieve good performance in the prediction of responders. Proteomic analysis of cancer tissues unveils molecular features that are associated with side effects in responders receiving combination therapy. In conclusion, our analysis identifies plasma features associated with uHCC responders to combination therapy. [Display omitted] • Responders have high plasma levels of complement proteins and LysoPCs • Responders have high tumor mutation burden • Responders are enriched for mutations in TP53 pathway • Machine learning models using metabolites classify responders and non-responders Li et al. demonstrate that patients with hepatocellular carcinoma who have high tumor mutation burden, high mutation in TP53 pathway, high plasma levels of certain complement proteins and LysoPCs, and low levels of certain immunoglobulins may respond to combination therapy with lenvatinib and anti-PD1 monoclonal antibody. [ABSTRACT FROM AUTHOR]

The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to challenge the efficacy of vaccination efforts against coronavirus disease 2019 (COVID-19). The Omicron XBB lineage of SARS-CoV-2 has presented dramatic evasion of neutralizing antibodies stimulated by mRNA vaccination and COVID-19 convalescence. XBB.1.16, characterized by two mutations relative to the dominating variant XBB.1.5, i.e., E180V and K478R, has been on the rise globally. In this study, we compare the immune escape of XBB.1.16 with XBB.1.5, alongside ancestral variants D614G, BA.2, and BA.4/5. We demonstrate that XBB.1.16 is strongly immune evasive, with extent comparable to XBB.1.5 in bivalent-vaccinated healthcare worker sera, 3-dose-vaccinated healthcare worker sera, and BA.4/5-wave convalescent sera. Interestingly, the XBB.1.16 spike is less fusogenic than that of XBB.1.5, and this phenotype requires both E180V and K478R mutations to manifest. Overall, our findings emphasize the importance of the continued surveillance of variants and the need for updated mRNA vaccine formulations. [Display omitted] • XBB.1.16 exhibits high extents of immune escape comparable to XBB.1.5 • XBB.1.16 escapes neutralizing antibodies in bivalent- and 3-dose-vaccinated sera • XBB.1.16 spike is less fusogenic than XBB.1.5 due to the E180V and K478R mutations • Higher infectivity of XBB.1.16 in 293T-ACE2 cells is driven by the K478R mutation SARS-CoV-2 continues to exhibit increasing immune escape. Here, Faraone et al. demonstrate that XBB.1.16 escapes antibodies in bivalent-vaccinated, 3-dose-vaccinated, and BA.4/5-wave convalescent sera to a similar extent compared with XBB.1.5. They also show that the XBB.1.16 spike is less fusogenic than XBB.1.5 but exhibits enhanced infectivity. [ABSTRACT FROM AUTHOR]

Omicron subvariants continuingly challenge current vaccination strategies. Here, we demonstrate nearly complete escape of the XBB.1.5, CH.1.1, and CA.3.1 variants from neutralizing antibodies stimulated by three doses of mRNA vaccine or by BA.4/5 wave infection, but neutralization is rescued by a BA.5-containing bivalent booster. CH.1.1 and CA.3.1 show strong immune escape from monoclonal antibody S309. Additionally, XBB.1.5, CH.1.1, and CA.3.1 spike proteins exhibit increased fusogenicity and enhanced processing compared with BA.2. Homology modeling reveals the key roles of G252V and F486P in the neutralization resistance of XBB.1.5, with F486P also enhancing receptor binding. Further, K444T/M and L452R in CH.1.1 and CA.3.1 likely drive escape from class II neutralizing antibodies, whereas R346T and G339H mutations could confer the strong neutralization resistance of these two subvariants to S309-like antibodies. Overall, our results support the need for administration of the bivalent mRNA vaccine and continued surveillance of Omicron subvariants. [Display omitted] • Bivalent booster induces 2- to 8-fold higher nAb titer than monovalent against XBB and XBB.1.5 • CH.1.1 and CA.3.1 exhibit nearly complete escape of neutralization from bivalent booster • XBB.1.5, CH.1.1, and CA.3.1 show increased fusogenicity compared with BA.2 • Homology modeling shows impacts of F486P mutation present in XBB.1.5 on ACE2 binding Qu et al. show that bivalent booster recipients, compared with monovalent recipients, exhibit higher nAb titers against Omicron subvariants XBB, XBB.1, and XBB.1.5. The CH.1.1 and CA.3.1 variants show more substantial neutralization escape than the XBB variants. Further, structural modeling reveals that the F486P mutation in XBB.1.5 enhances ACE2 binding. [ABSTRACT FROM AUTHOR]

Summary The interferon-induced transmembrane (IFITM) proteins have been recently shown to restrict HIV-1 and other viruses. Here, we provide evidence that IFITM proteins, particularly IFITM2 and IFITM3, specifically antagonize the HIV-1 envelope glycoprotein (Env), thereby inhibiting viral infection. IFITM proteins interact with HIV-1 Env in viral producer cells, leading to impaired Env processing and virion incorporation. Notably, the level of IFITM incorporation into HIV-1 virions does not strictly correlate with the extent of inhibition. Prolonged passage of HIV-1 in IFITM-expressing T lymphocytes leads to emergence of Env mutants that overcome IFITM restriction. The ability of IFITMs to inhibit cell-to-cell infection can be extended to HIV-1 primary isolates, HIV-2 and SIVs; however, the extent of inhibition appears to be virus-strain dependent. Overall, our study uncovers a mechanism by which IFITM proteins specifically antagonize HIV-1 Env to restrict HIV-1 infection and provides insight into the specialized role of IFITMs in HIV infection. [ABSTRACT FROM AUTHOR]

Despite remarkable advances in treatment, most patients with hepatocellular carcinoma (HCC) respond poorly to anti-programmed cell death 1 (anti-PD1) therapy. A deeper insight into the tolerance mechanism of HCC against this therapy is urgently needed. We performed next-generation sequencing, multiplex immunofluorescence, and dual-color immunohistochemistry and constructed an orthotopic HCC xenograft tumor model to identify the key gene associated with anti-PD1 tolerance. A spontaneously tumorigenic transgenic mouse model, an in vitro coculture system, mass cytometry, and multiplex immunofluorescence were used to explore the biological function of zinc finger protein 64 (ZFP64) on tumor progression and immune escape. Molecular and biochemical strategies like RNA-sequencing, chromatin immunoprecipitation-sequencing and mass spectrometry were used to gain insight into the underlying mechanisms of ZFP64. We showed that ZFP64 is frequently upregulated in tumor tissues from patients with anti-PD1-resistant HCC. Elevated ZFP64 drives anti-PD1 resistance by shifting macrophage polarization toward an alternative activation phenotype (M2) and fostering an inhibitory tumor microenvironment. Mechanistically, we primarily demonstrated that protein kinase C alpha (PKCα) directly phosphorylates ZFP64 at S226, leading to its nuclear translocation and the transcriptional activation of macrophage colony-stimulating factor (CSF1). HCC-derived CSF1 transforms macrophages to the M2 phenotype to drive immune escape and anti-PD1 tolerance. Notably, Gö6976, a protein kinase inhibitor, and lenvatinib, a multi-kinase inhibitor, reset the tumor microenvironment and restore sensitivity to anti-PD1 by blocking the PKCα/ZFP64/CSF1 axis. We propose that the PKCα/ZFP64/CSF1 axis is critical for triggering immune evasion and anti-PD1 tolerance. Inhibiting this axis with Gö6976 or lenvatinib overcomes anti-PD1 resistance in HCC. Despite remarkable treatment progress, most patients with hepatocellular carcinoma respond poorly to anti-PD1 therapy (a type of immunotherapy). A deeper insight into the tolerance mechanisms to this therapy is urgently needed. Herein, we unravel a previously unexplored mechanism linking tumor progression, macrophage polarization, and anti-PD1 resistance, and offer an attractive novel target for anti-PD1 combination therapy, which may benefit patients with hepatocellular carcinoma. [Display omitted] • ZFP64 is frequently upregulated in anti-PD1 resistant HCC. • PKCα/ZFP64/CSF1 axis is critical for triggering immune evasion and anti-PD1 tolerance. • Gö6976 and lenvatinib overcome anti-PD1 resistance by blocking the PKCα/ZFP64/CSF1 axis. • Gö6976 combined with anti-PD1 could be an effective new strategy in HCC therapy. [ABSTRACT FROM AUTHOR]

Abstract: Nardokanshone A (1), a new type of sesquieterpenoid–chalcone hybird, with a 2,3-dihydrofuran ring fusing an aristolane-type sesquiterpenoid and a chalcone, along with its possible bioprecursor, kanshone C (2), together with four known flavones were isolated from Nardostachys chinensis. Their structures were elucidated by spectroscopic methods, and the absolute configuration of 1 was determined by quantum chemical DFT calculations. The possible biosynthetic pathway of 1 was also proposed. [Copyright &y& Elsevier]