Using recombinant antigen variant-expressing chronic LCMV strains, Zehn and colleagues showed that amount rather than antigen strength is a key determinant of inducing a chronic infection phenotype in T cells.

Viral infections lead to alarmin release and elicit potent cytotoxic effector T lymphocyte (CTLeff) responses. Conversely, the induction of protective tumour-specific CTLeff and their recruitment into the tumour remain challenging tasks. Here we show that lymphocytic choriomeningitis virus (LCMV) can be engineered to serve as a replication competent, stably-attenuated immunotherapy vector (artLCMV). artLCMV delivers tumour-associated antigens to dendritic cells for efficient CTL priming. Unlike replication-deficient vectors, artLCMV targets also lymphoid tissue stroma cells expressing the alarmin interleukin-33. By triggering interleukin-33 signals, artLCMV elicits CTLeff responses of higher magnitude and functionality than those induced by replication-deficient vectors. Superior anti-tumour efficacy of artLCMV immunotherapy depends on interleukin-33 signalling, and a massive CTLeff influx triggers an inflammatory conversion of the tumour microenvironment. Our observations suggest that replicating viral delivery systems can release alarmins for improved anti-tumour efficacy. These mechanistic insights may outweigh safety concerns around replicating viral vectors in cancer immunotherapy.

BackgroundRespiratory syncytial virus (RSV) is associated with significant mortality rates amongst hematopoietic stem cell transplant (HSCT) recipients, with less known about other immunocompromised patients.MethodsTen-year retrospective cohort study of immunocompromised patients presenting with RSV disease documented at University Hospitals of Lausanne and Geneva. Severe RSV-related outcomes referred to RSV documented respiratory conditions requiring hospital admission, presenting as lower respiratory tract infection (LRTI) or pneumonia. We used multivariable logistic regression to assess clinical and laboratory correlates of severe RSV disease.ResultsFrom 239 RSV-positive immunocompromised in and out-patients 175 were adults and 64 children of whom 111 (47.8%) presented with LRTI, which resulted in a 38% (89/239) admission rate to hospital. While immunocompromised children were more likely to be admitted to hospital compared to adults (75% vs 62.9%, p = 0.090), inpatients admitted to the intensive care unit (17/19) or those who died (11/11) were mainly adults. From multivariable analyses, adults with solid tumors (OR 5.2; 95% CI: 1.4–20.9 P = 0.015) or those requiring chronic immunosuppressive treatments mainly for rheumatologic conditions (OR 4.1; 95% CI: 1.1–16.0; P = 0.034) were significantly more likely to be admitted to hospital compared to hematopoietic stem cell (HSCT) recipients. Bacterial co-infection was significantly and consistently associated with viral LRTI and pneumonia.ConclusionsFrom our findings, RSV-related disease results in a significant burden among adults requiring chronic immunosuppressive treatments for rheumatological conditions and those with solid tumors. As such, systematic screening for respiratory viruses, should be extended to other immunocompromised populations than HSCT recipients.Electronic supplementary materialThe online version of this article (10.1186/s12879-018-3002-3) contains supplementary material, which is available to authorized users.

Highlights d Engineered arenaviruses induce potent tumor self-specific CD8 T cell (CTL) response d Combinations of distantly but not closely related arenavirus vectors eliminate tumors d Vector backbone-targeted CTL responses compete against tumor self-reactive CTLs

a b s t r a c tIn recent years, considerable research has focused on the biological effect of endocrine-disrupting chemicals. Bisphenol A (BPA) has been implicated as an endocrine-disrupting chemical (EDC) due to its ability to mimic the action of endogenous estrogenic hormones.The aim of this study was to assess the effect of perinatal exposure to BPA on cerebral structural development and metabolism after birth.BPA (1 mg/l) was administered in the drinking water of pregnant dams from day 6 of gestation until pup weaning. At postnatal day 20, in vivo metabolite concentrations in the rat pup hippocampus were measured using high field proton magnetic resonance spectroscopy. Further, brain was assessed histologically for growth, gross morphology, glial and neuronal development and extent of myelination.Localized proton magnetic resonance spectroscopy ( 1 H MRS) showed in the BPA-exposed rat a significant increase in glutamate concentration in the hippocampus as well as in the Glu/Asp ratio. Interestingly these two metabolites are metabolically linked together in the malate-aspartate metabolic shuttle.Quantitative histological analysis revealed that the density of NeuN-positive neurons in the hippocampus was decreased in the BPA-treated offspring when compared to controls. Conversely, the density of GFAP-positive astrocytes in the cingulum was increased in BPA-treated offspring.In conclusion, exposure to low-dose BPA during gestation and lactation leads to significant changes in the Glu/Asp ratio in the hippocampus, which may reflect impaired mitochondrial function and also result in neuronal and glial developmental alterations.

c Recombinant glycoprotein-deficient lymphocytic choriomeningitis virus-based vaccine vectors (rLCMV/⌬GP) are potent CD8 ؉ T cell inducers. To investigate the underlying molecular requirements, we generated a nucleoprotein-deficient vector counterpart (rLCMV/⌬NP). NP but not GP is a minimal trans-acting factor for viral transcription and genome replication. We found that, unlike rLCMV/⌬GP, rLCMV/⌬NP failed to elicit detectable CD8 ؉ T cell responses unless NP was trans complemented in a transgenic host. Hence, NP-dependent intracellular gene expression is essential for LCMV vector immunogenicity. Lymphocytic choriomeningitis virus (LCMV), the prototypic arenavirus, has a negative-strand RNA genome with two segments, designated S and L, each of which carries two viral genes in ambisense orientation (wild-type LCMV [LCMV wt]) ( Fig. 1A) (1). Viral particles contain S and L ribonucleoproteins (RNP) wherein the genomic RNAs are encapsidated by the nucleoprotein (NP) in association with the RNA-dependent RNA polymerase (RdRp) L. NP and L represent the minimal viral trans-acting factors for viral RNA transcription and replication (Fig. 1B), whereas the glycoprotein (GP) mediates receptor binding and cell entry (2, 3). Upon RNP release to the cytoplasm, the virion-contained RdRp initiates NP and L mRNA transcription from the 3= untranslated region (UTR) promoters of the NP-encapsidated S and L segments (Fig. 1B), respectively, a process that is independent of de novo viral protein synthesis. Conversely, de novo NP synthesis is required for encapsidation of the nascent antigenome RNA species for them to serve as the templates for GP and Z mRNA transcription, respectively, and genome replication.We have previously shown that deletion of the viral glycoprotein gene (GP) and its replacement by sequences encoding vaccine antigens offers a strategy to generate single-round infectious vaccine vectors (recombinant GP-deficient LCMV [rLCMV/⌬GP]) (Fig. 1A) (4-6). The production of infectious rLCMV/⌬GP by pseudotyping requires GP-expressing cell lines (e.g., stably GPexpressing BHK-21 cells [BHK-GP]). In the vaccinees, the lack of de novo GP synthesis prevents vector spread. Nevertheless, rLCMV/⌬GP induces polyfunctional and protective CD8 ϩ T cell responses that reach a sizeable magnitude at doses as low as 300 PFU (4).Here, we studied the viral molecular requirements for immunogenicity of single-round infectious LCMV vectors. Contrary to the notion that CD8 ϩ T cell-inducing vaccines should produce antigens in cells of the vaccinee for direct presentation on major histocompatibility complex (MHC) class I (7), hydrogen peroxide-inactivated LCMV has recently been shown to induce protective CD8 ϩ T cell immunity (8-10). Whether this reflects residual translation of viral proteins in the absence of productive replication or cross-presentation of particle-derived proteins remains undefined (9). Here, we tested specifically whether rLCMV vector immunogenicity depends on de novo synthesis of NP in vivo, which is required for viral gen...

Mycobacterium tuberculosis (Mtb) represents a major burden to global health, and refined vaccines are needed. Replication-deficient lymphocytic choriomeningitis virus (rLCMV)-based vaccine vectors against cytomegalovirus have proven safe for human use and elicited robust T cell responses in a large proportion of vaccine recipients. Here, we developed an rLCMV vaccine expressing the Mtb antigens TB10.4 and Ag85B. In mice, rLCMV elicited high frequencies of polyfunctional Mtb-specific CD8 and CD4 T cell responses. CD8 but not CD4 T cells were efficiently boosted upon vector re-vaccination. High-frequency responses were also observed in neonatally vaccinated mice, and co-administration of rLCMV with Expanded Program of Immunization (EPI) vaccines did not result in substantial reciprocal interference. Importantly, rLCMV immunization significantly reduced the lung Mtb burden upon aerosol challenge, resulting in improved lung ventilation. Protection was associated with increased CD8 T cell recruitment but reduced CD4 T cell infiltration upon Mtb challenge. When combining rLCMV with BCG vaccination in a heterologous prime-boost regimen, responses to the rLCMV-encoded Mtb antigens were further augmented, but protection was not significantly different from rLCMV or BCG vaccination alone. This work suggests that rLCMV may show utility for neonatal and/or adult vaccination efforts against pulmonary tuberculosis.

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