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The limited host tropism of numerous viruses causing disease in humans remains incompletely understood. One example is Zika virus (ZIKV), an RNA virus that has reemerged in recent years. Here, we demonstrate that ZIKV efficiently infects fibroblasts from humans, great apes, New and Old World monkeys, but not rodents. ZIKV infection in human—but not murine—cells impairs responses to agonists of the cGMP-AMP synthase/stimulator of IFN genes (cGAS/STING) signaling pathway, suggesting that viral mechanisms to evade antiviral defenses are less effective in rodent cells. Indeed, human, but not mouse, STING is subject to cleavage by proteases encoded by ZIKV, dengue virus, West Nile virus, and Japanese encephalitis virus, but not that of yellow fever virus. The protease cleavage site, located between positions 78/79 of human STING, is only partially conserved in nonhuman primates and rodents, rendering these orthologs resistant to degradation. Genetic disruption of STING increases the susceptibility of mouse—but not human—cells to ZIKV. Accordingly, expression of only mouse, not human, STING in murine STING knockout cells rescues the ZIKV suppression phenotype. STING-deficient mice, however, did not exhibit increased susceptibility, suggesting that other redundant antiviral pathways control ZIKV infection in vivo. Collectively, our data demonstrate that numerous RNA viruses evade cGAS/STING-dependent signaling and affirm the importance of this pathway in shaping the host range of ZIKV. Furthermore, our results explain—at least in part—the decreased permissivity of rodent cells to ZIKV, which could aid in the development of mice model with inheritable susceptibility to ZIKV and other flaviviruses.

The objective of our study was to report real-world data on the safety and efficacy of standard-of-care teclistamab in patients with relapsed/refractory multiple myeloma (MM). This is a multi-institutional retrospective cohort study and included all consecutive patients that received at least one dose of teclistamab up until August 2023. One hundred and ten patients were included, of whom, 86% had triple-class refractory disease, 76% penta-refractory disease, and 35% had prior exposure to B-cell maturation antigen (BCMA)-targeting therapies. The overall response rate (ORR) in our cohort was 62%, with a ≥ very good partial remission (VGPR) rate of 51%. The ORR in patients with and without prior BCMA-targeted therapies was 54% vs 67%, respectively ( p  = 0.23). At a median follow-up of 3.5 months (range, 0.39–10.92), the estimated 3 month and 6 month progression free survival (PFS) was 57% (95% CI, 48%, 68%) and 52% (95% CI, 42%, 64%) respectively. The incidence of cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) was 56% and 11% respectively, with grade ≥3 CRS and ICANS noted in 3.5% and 4.6% of patients respectively. 78 unique infections were diagnosed in 44 patients, with the incidence of all-grade and grade ≥3 infections being 40% vs 26% respectively. Primary prophylaxis with intravenous immunoglobulin (IVIG) was associated with a significantly lower infection risk on multivariate analysis (Hazard ratio [HR] 0.33; 95% CI 0.17, 0.64 ; p  = 0.001).

Resistance to regeneration of insulin-producing pancreatic β cells is a fundamental challenge for type 1 and type 2 diabetes. Recently, small molecule inhibitors of the kinase DYRK1A have proven effective in inducing adult human β cells to proliferate, but their detailed mechanism of action is incompletely understood. We interrogated our human insulinoma and β cell transcriptomic databases seeking to understand why β cells in insulinomas proliferate, while normal β cells do not. This search reveals the DREAM complex as a central regulator of quiescence in human β cells. The DREAM complex consists of a module of transcriptionally repressive proteins that assemble in response to DYRK1A kinase activity, thereby inducing and maintaining cellular quiescence. In the absence of DYRK1A, DREAM subunits reassemble into the pro-proliferative MMB complex. Here, we demonstrate that small molecule DYRK1A inhibitors induce human β cells to replicate by converting the repressive DREAM complex to its pro-proliferative MMB conformation.

The restricted host tropism of hepatitis C virus (HCV) remains incompletely understood, especially post-entry, and has hindered developing an immunocompetent, small animal model. HCV replication in non-permissive species may be limited by incompatibilities between the viral replication machinery and orthologs of essential host factors, like cyclophilin A (CypA). We thus compared the ability of CypA from mouse, tree shrew, and seven non-human primate species to support HCV replication, finding that murine CypA only partially rescued viral replication in Huh7.5-shRNA CypA cells. We determined the specific amino acid differences responsible and generated mutants able to fully rescue replication. We expressed these mutants in engineered murine hepatoma cells and although we observed increases in HCV replication following infection, they remained far lower than those in highly permissive human hepatoma cells, and minimal infectious particle release was observed. Together, these data suggest additional co-factors remain unidentified. Future work to determine such factors will be critical for developing an immunocompetent mouse model supporting HCV replication. Hepatitis C is a life-long disease that begins when a virus infects the cells of the liver. Although the infection is curable, it is expensive to treat, and there is not yet a vaccine to prevent the disease. This is largely because the virus that causes hepatitis C, also known as HCV, naturally only infects humans and chimpanzees, which has made it difficult to generate an effective animal model for developing a vaccine. Mice are frequently used as a model for studying disease and can be genetically altered to allow HCV to enter their liver cells. However, once HCV enters mouse cells, it struggles to replicate. As a result, an infection does not develop, and the immune system’s response to the virus cannot be fully explored. Replication of HCV in humans relies on a protein called cyclophilin A, or CypA for short. Now, Gaska et al. have set out to improve current animal models for HCV by investigating whether HCV can also use CypA from other species, including mice, to replicate. Gaska et al. showed that the mouse form of CypA could help HCV replicate in human liver cells with lower than normal levels of CypA, but only very poorly. Editing the mouse gene for CypA to be more like the human version resulted in higher HCV replication. Putting variants of CypA into the liver cells of mice, which do not normally replicate HCV at high levels, led to an increase in HCV replication. However, replication of HCV in mice was still far lower than in human liver cells, suggesting that the mouse model system could be improved by learning more about which proteins interact with CypA. Injection drug use – one of the main ways hepatitis C spreads – is becoming increasingly common because of the growing opioid epidemic in many countries. A clinically relevant animal model that supports hepatitis C virus infection would be an important milestone towards a vaccine that could prevent the continued spread of this disease.

The main objective of this multi-institutional study is to understand the effect of primary intravenous immunoglobulin (IVIG) replacement on clinical outcomes in recipients of BCMA-directed bispecific antibody (bsAb), where infection remains an important cause of morbidity and mortality. This is a retrospective study of patients treated with either standard of care teclistamab or BCMA-directed investigational bsAb between Nov 2017 and Dec 2023. Primary IVIG prophylaxis was defined as starting IVIG prior to first documented infection. All analyses were adjusted for immortal-time bias inherent in this grouping. A total of 225 patients were included in this analysis. Primary IVIG prophylaxis was defined as starting IVIG prior to first documented infection. The median follow-up of patients treated with and without primary IVIG prophylaxis was, 9 and 11 months, respectively. The cumulative incidence of all grade infections at 12 months with and without primary IVIG prophylaxis were 56% (95%CI 40%,78%) and 60% (95% CI 48%, 76%); p  = 0.72, respectively. The 12-month cumulative incidence of ≥ grade 3 infections was 35% (95% CI 21%, 57%) with primary IVIG prophylaxis and 45% (95% CI 34%, 60%) without; p  = 0.37. The median infection free survival (IFS) for all-grade infections was 7.7 (95% CI 3.3, 14) months with primary IVIG prophylaxis and 3 (95% CI 2.6, 4.5) months without ( p  = 0.021). The median ≥ grade 3 IFS was 14 (95% CI 8.8, NR) and 7.5 (95% CI 6.1, 14) months, with and without primary IVIG respectively; p  = 0.022. Patients on primary IVIG prophylaxis had a superior progression-free-survival (PFS) [median PFS 15 vs 8 months; p  = 0.026] and overall-survival (OS) [median OS 16 vs 44 months; p  = 0.007]. On multivariate analysis, primary IVIG prophylaxis was independently associated with improved OS (HR = 0.37; p  = 0.021), while the presence of extra-medullary (HR = 2.71; p  = <0.001) and high-risk disease (HR = 1.88; p  = 0.031) conferred poor outcomes. In recipients of BCMA-directed bsAb, IVIG supplementation was associated with an improved clinical outcome, including favorable IFS and OS.

Differences in immune responses across species can contribute to the varying permissivity of species to the same viral pathogen. Understanding how our closest evolutionary relatives, nonhuman primates (NHPs), confront pathogens and how these responses have evolved over time could shed light on host range barriers, especially for zoonotic infections. Here, we analyzed cell-intrinsic immunity of primary cells from the broadest panel of NHP species interrogated to date, including humans, great apes, and Old and New World monkeys. Our analysis of their transcriptomes after poly(I:C) transfection revealed conservation in the functional consequences of their response. In mapping reads to either the human or the species-specific genomes, we observed that with the current state of NHP annotations, the percent of reads assigned to a genetic feature was largely similar regardless of the method. Together, these data provide a baseline for the cell-intrinsic responses elicited by a potent immune stimulus across multiple NHP donors, including endangered species, and serve as a resource for refining and furthering the existing annotations of NHP genomes.

Resistance to regeneration of insulin-producing pancreatic [beta] cells is a fundamental challenge for type 1 and type 2 diabetes. Recently, small molecule inhibitors of the kinase DYRK1A have proven effective in inducing adult human [beta] cells to proliferate, but their detailed mechanism of action is incompletely understood. We interrogated our human insulinoma and [beta] cell transcriptomic databases seeking to understand why [beta] cells in insulinomas proliferate, while normal [beta] cells do not. This search reveals the DREAM complex as a central regulator of quiescence in human [beta] cells. The DREAM complex consists of a module of transcriptionally repressive proteins that assemble in response to DYRK1A kinase activity, thereby inducing and maintaining cellular quiescence. In the absence of DYRK1A, DREAM subunits reassemble into the pro-proliferative MMB complex. Here, we demonstrate that small molecule DYRK1A inhibitors induce human [beta] cells to replicate by converting the repressive DREAM complex to its pro-proliferative MMB conformation.