Human cytomegalovirus (HCMV) is a widely spread herpesvirus, suggested to play a role in tumor progression. US28, a chemokine receptor encoded by HCMV, binds a broad spectrum of chemokines and constitutively activates various pathways linked to proliferation. Our studies reveal that expression of US28 induces a proangiogenic and transformed phenotype by up-regulating the expression of vascular endothelial growth factor and enhancing cell growth and cell cycle progression. US28-expressing cells promote tumorigenesis when injected into nude mice. The G proteinuncoupled constitutively inactive mutant of US28, induces delayed and attenuated tumor formation, indicating the importance of constitutive receptor activity in the early onset of tumor development. Importantly, also in glioblastoma cells infected with the newly isolated clinical HCMV strain Titan, US28 was shown to be involved in the HCMV-induced angiogenic phenotype. Hence, the constitutively activated chemokine receptor US28 might act as a viral oncogene and enhance and͞or promote HCMV-associated tumor progression.cancer ͉ G protein-coupled receptor ͉ VEGF ͉ viral infection ͉ drug target

Taken together, the streptamer technology offers the advantage of selecting virus-specific CD8+ T cells at GMP level for adoptive T-cell transfer, thus inducing long-lasting specific CD8+ T-cell responses without increasing the risk for graft-versus-host disease.

The human cytomegalovirus (HCMV), potentially associated with the development of malignancies, encodes the constitutively active chemokine receptor US28. Previously, we have shown that US28 expression induces an oncogenic phenotype both in vitro and in vivo. Microarray analysis revealed differential expression of genes involved in oncogenic signaling in US28-expressing NIH-3T3 cells. In particular, the expression of cyclooxygenase-2 (COX-2), a key mediator of inflammatory diseases and major determinant in several forms of cancer, was highly up-regulated. US28 induced increases in COX-2 expression via activation of nuclear factor-KB, driving the production of vascular endothelial growth factor. Also, in HCMV-infected cells, US28 contributed to the viral induction of COX-2. Finally, the involvement of COX-2 in US28-mediated tumor formation was evaluated using the COX-2 selective inhibitor Celecoxib. Targeting COX-2 in vivo with Celecoxib led to a marked delay in the onset of tumor formation in nude mice injected with US28-transfected NIH-3T3 cells and a reduction of subsequent growth by repressing the US28-induced angiogenic activity. Hence, the development of HCMV-related proliferative diseases may partially be ascribed to the ability of US28 to activate COX-2.

Coronavirus disease 2019 (COVID-19) is a viral infection caused by the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), which spreads rapidly from person to person and manifests in most symptomatic patients as a respiratory illness, similar to prior SARS viruses. Neurologic manifestations of COVID-19 are uncommon; those so far reported include encephalopathy, stroke from large-vessel occlusion, and polyneuropathy. We report a unique neurologic complication of COVID-19 in a patient who had extensive cerebral small-vessel ischemic lesions resembling cerebral vasculitis in a characteristic combined imaging pattern of ischemia, hemorrhage, and punctuate postcontrast enhancement. Also, a characteristic lower extremity skin rash was present in our patient. Our observation lends support to the increasingly suspected mechanism of "endotheliitis" associated with this novel coronavirus.

The resurrection plant Craterostigma plantagineum tolerates an extreme loss of cellular water. Therefore this plant is being studied as model system to analyse desiccation tolerance at the molecular level. Upon dehydration, new transcripts are abundantly expressed in different tissues of the plant. One such desiccation‐related nuclear gene (dsp‐22 for desiccation stress protein) encodes a mature 21 kDa protein which accumulates in the chloroplasts. Sequence analysis indicates that dsp‐22 is closely related to early light inducible genes (Elip) of higher plants and to a carotene biosynthesis related gene (cbr) isolated from the green alga Dunaliella bardawil. In contrast to other desiccation‐related genes, light is an essential positive factor regulating the expression of dsp‐22: ABA‐mediated gene activation leads to the accumulation of the transcript only in the presence of light. During the desiccation process, light acts at the transcriptional and post‐transcriptional levels. The implications of these different controls and the possible role of the dsp‐22 protein in the desiccation/rehydration process are discussed.

We have investigated the morphogenesis of human and murine cytomegalovirus by transmission electron microscopy after high-pressure freezing, freeze substitution, and plastic embedding. We observed large tubular infoldings of the inner nuclear membrane that were free of lamina and active in primary envelopment and subsequent transport of capsids to the nuclear periphery. Semiquantitative determinations of the enlarged inner nuclear membrane area and the location of the primary envelopment of nucleocapsids demonstrated that this structure represents a virus-induced specialized membrane domain at which the particles are preferentially enveloped. This is a previously undescribed structural element relevant in cytomegalovirus morphogenesis.Murine cytomegalovirus (MCMV) and human CMV (HCMV) are members of the Betaherpesvirinae. Both viruses encode more than 200 open reading frames (15). The morphogenesis of herpesviruses is a complex process involving multiple interactions between viral and cellular components, especially membranes, and thus is of high interest for both virology and cell biology. The stepwise assembly of the virion has been studied extensively in alphaherpesviruses (10,11,18,20). However, much less is known about the morphogenesis of CMVs (3,12). When the findings from alphaherpesviruses are compared with those from cytomegaloviruses, it has to be kept in mind that the sequence homology is only partial and that the latter viruses have a larger coding capacity. Since the size of all herpesvirus capsids prevents their transport into the cytoplasm through the nuclear pore complex, nuclear egress requires the penetration of the nuclear membranes and the nuclear lamina, probably through an envelopment/de-envelopment process, which is still under debate (11,24). This may also be different for CMVs, since the involved alphaherpesviral kinase US3 is not conserved in betaherpesviruses (7, 16). For MCMV, it has been shown that the viral protein M50 inserts into the inner nuclear membrane and is aggregated by a second viral protein, M53, to form the putative capsid docking site (13). M50 then recruits cellular protein kinases for phosphorylation and dissolution of the nuclear lamina. Additionally, it has been shown for HCMV that pUL97 in concert with the cellular p32 acts by the redistribution of lamina components (9). While the list of viral proteins involved in this process is growing, little ultrastructural information on nuclear egress is available. After release to the cytoplasm, CMV capsids are tegumented and enveloped at Golgi apparatus-derived cisternae (6) by a wrapping process and released by fusion with the plasma membrane.We have investigated cytomegalovirus nuclear egress by electron microscopy using high-pressure freezing, freeze substitution, and plastic embedding. Fibroblast cell monolayers (3T3 murine fibroblasts for MCMV or human foreskin fibroblasts for HCMV) were grown on carbon-coated sapphire discs (3-mm diameter; Engineering Office M. Wohlwend GmbH, Switzerland) and infected at a multiplic...

SummaryCytomegalovirus (CMV) infection remains a significant cause of morbidity and mortality in transplant recipients. Letermovir (AIC246), is a novel anti-HCMV drug in development, acting via a novel mechanism of action. In this proof-ofconcept trial with first administration of letermovir to patients, 27 transplant recipients with active CMV replication were randomly assigned to a 14-day oral treatment regimen of either letermovir 40 mg twice a day, letermovir 80 mg once a day, or local standard of care (SOC) in a multicenter, open-label trial. Efficacy, safety, and limited pharmacokinetic parameters were assessed. All groups had a statistically significant decrease in CMV-DNA copy number from baseline (40 mg BID: P = 0.031; 80 mg QD: P = 0.018; SOC: P = 0.001), and comparison of viral load reduction between treatment groups showed no statistically significant differences. Viral clearance was achieved for 6 of 12 patients (50%) in the letermovir groups versus two of seven SOC patients (28.6%). Letermovir treatment was generally well tolerated, no patient developed CMV disease during the trial. Both letermovir treatment regimens resulted in equally high trough level plasma concentrations. The efficacy, safety, and pharmacokinetics observed in these viremic transplant recipients indicate that letermovir is a promising new anti-CMV drug.

The resurrection plant Craterostigma plantagineum can recover from severe desiccation within 24 h of contact with water, and it is used as a model system to analyse desiccation tolerance in higher plants. During drying or ABA treatment a specific set of transcripts accumulates rapidly in leaves and other tissues. In order to study transcriptional mechanisms of stress-induced gene expression one gene (CDeT27-45) was selected for promoter analysis. Chimeric gene fusions were constructed of the CDeT27-45 promoter and beta-glucuronidase or luciferase. These constructs were tested in a homologous transient expression system which allowed the identification of promoter elements conferring ABA inducibility. By introducing the chimeric gene fusions into tobacco via Agrobacterium-mediated transformation we found that the promoter activity is under strict tissue-specific and developmental control. In tobacco the promoter was only active in developing embryos and in mature pollen grains-two tissues which are naturally desiccation tolerant in tobacco. The specific temporal expression pattern was attributed to particular 5' upstream sequences. The promoter analysis presented here should allow the separation of important regulatory components as a first step in dissecting events in the signal transduction chain.