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PubMedDate not supplied

The association of the temperature-sensitive phenotype with viral attenuation in animals and humans: implications for the development and use of live virus vaccines.

Viruses that possess temperature-sensitive mutations are consistently attenuated in vivo compared with the wild-type parental strains. Such temperature-sensitive (ts) mutants are currently used in several live attenuated virus vaccines and have been proposed for use against several additional viral diseases, including influenza. This paper reviews the following: (1) the evidence that the ts mutation itself is responsible for attenuation; (2) experimental infection of animals and humans with ts mutant viruses; (3) the experience of humans with naturally occurring ts mutants; and (4) the rationale for the use of ts mutants in live virus vaccines. In addition, the potential of ts mutants to produce altered patterns of disease is considered. After the known and potential benefits and possible risks involved in the use of ts mutant viruses are weighed, the continuing use and development of vaccines using live attenuated ts virus seems warranted.

Animals↗
PubMed1977

[Test of an attenuated viral strain of TGE as a vaccine].

A live vaccine was produced using a local strain P of the virus of the transmissive gastroenteritis, arrenuated in cell cultures. The vaccinated pregnant sows had high-titer serum and colostrum virus-neutralizing antibodies. In the first days following farrowing there were in the colostrum ummunoglobulins of the Igg class that prevailed, however, IgA and IgM proved more effective in the virus-neutralizing test. Newborn pigs acquired passive immunity at about the 24th hour after the intake of colostrum. They withstood a challenge with a virulent virus.

Animals↗
PubMed2026

PRRSV suppresses FTO-dependent m6A demethylation to reprogram STAT signaling and innate immunity.

RNA viruses have evolved diverse strategies to evade host interferon (IFN)-stimulated gene (ISG) defenses; however, how they exploit host epitranscriptomic regulation remains poorly understood. Here, we identify an immune-evasion mechanism in which porcine reproductive and respiratory syndrome virus (PRRSV) targets the m6A demethylase fat mass and obesity-associated protein (FTO) to suppress antiviral signaling. Mechanistically, the viral endoribonuclease nsp11 inhibits STAT5-dependent transcription through the key residues Q96 and S104, thereby reducing FTO expression. Loss of FTO increases m6A modification of STAT2 and STAT3 transcripts, impairing their translation and phosphorylation, thereby attenuating ISG responses. Reduced STAT3 activity further dampens STAT5 signaling, establishing a feed-forward circuit that amplifies suppression of antiviral immunity. Functionally, disruption of this regulatory region (Q96A and S104A) attenuates viral pathogenicity in vivo and restores ISG induction. These mutations also reduce infection-associated inflammatory responses and the accumulation of reactive oxygen species. Together, these findings define a nsp11-STAT5-FTO-STAT2/3 axis that enables PRRSV to reprogram host epitranscriptomic control of innate immunity. Our work reveals a mechanism of epitranscriptomic hijacking and identifies FTO as a key host factor exploited by RNA viruses, highlighting m6A regulation as a potential target for antiviral intervention.IMPORTANCEViruses must overcome host innate immune defenses to establish infection; however, the mechanisms by which they manipulate host RNA regulation remain incompletely understood. In this study, we show that porcine reproductive and respiratory syndrome virus (PRRSV) suppresses interferon responses by targeting the host m6A demethylase FTO through its endoribonuclease nsp11. This process involves the inhibition of STAT5 phosphorylation, which reduces FTO expression and increases m6A modification of key immune regulators, including STAT2 and STAT3, thereby impairing their activation. Disruption of this pathway attenuates viral pathogenicity in vivo and restores antiviral signaling. These results demonstrate that PRRSV can reprogram host epitranscriptomic regulation to modulate innate immunity and suggest that m6A-related pathways may be potential targets for antiviral intervention.

Immunity, Innate↗
PubMed2025

N6-methyladenosine modification of the subgroup J avian leukosis viral RNAs attenuates host innate immunity via MDA5 signaling.

Subgroup J avian leukosis virus (ALV-J), a retrovirus, elicits immunosuppression and persistent infections in chickens. Although it is widely acknowledged that ALV-J can evade the host's innate immune defenses, the mechanisms behind this immune evasion remain elusive. N6-methyladenosine (m6A), the most prevalent internal RNA modification, plays a role in innate immune evasion. Our research identified ALV-J as an inefficient stimulator of innate immunity in vitro and in vivo, with its genomic RNA featuring m6A modifications predominantly in the envelope protein (Env) region and 3' untranslated region (3'UTR). To elucidate the functional consequences of m6A modification, we subsequently generated m6A-deficient ALV-J through its culturing in the DF-1 overexpressing fat mass and obesity-associated protein (FTO) cells. The m6A-deficient ALV-J virus, or its RNAs significantly enhanced IFN-β production compared to the wild-type (wt) ALV-J, suggesting a pivotal regulatory function of m6A modifications in modulating innate immune response. Mechanistically, the m6A modification of the ALV-J genomic RNA directly impacted its recognition by MDA5, weakening its binding and ubiquitination and attenuating IFN-β activation. Moreover, m6A-deficient ALV-J, created by inducing mutations in m6A sites within Env and 3'UTR, exhibited reduced replication capacity and elevated IFN-β expression in host cells. Importantly, this phenomenon was abolished in MDA5-knockout DF-1 cells, further demonstrating the core role of MDA5. These data demonstrate that m6A modification of ALV-J genomic RNA dampens the host's innate immune response through MDA5 signaling pathway.

Animals↗
PubMed2026

Small molecule inhibition of the mitochondrial lipid transfer protein STARD7 attenuates influenza viral replication.

The increasing appearance of drug-resistant and zoonotic influenza strains highlights an urgent need for host-directed antivirals that offer broad-spectrum activity and a higher barrier to resistance. Here, we describe the characterization of M4, a small-molecule identified from a high-throughput screen that potently inhibits influenza A and B viruses. Mechanistic studies reveal that M4 suppresses influenza virus replication by preventing formation of export-competent viral ribonucleoprotein (vRNP) complexes in the nucleus. Chemoproteomic profiling identified the lipid transfer protein STARD7 as the primary cellular target, and genetic depletion of STARD7 phenocopies the antiviral effects of M4. Additional studies localized the M4 binding site to cysteine 302 within the lipid-binding domain of STARD7, supporting a model in which STARD7-dependent lipid transfer activity promotes efficient vRNP assembly and nuclear export. Combining M4 with baloxavir enhances antiviral efficacy in a murine infection model, providing in vivo support for a host-directed therapeutic strategy. Together, these results identify STARD7 as a metabolic checkpoint licensing vRNP nuclear export and they establish a proof of concept for therapeutic intervention with small molecule inhibitors.

Journal Article↗
PubMed2026

Recent advances for the pharmaceutical production of highly attenuated poxviruses as viral vector platforms.

INTRODUCTION: Highly attenuated poxviruses serve as potent viral vectors, oncolytic agents, and therapeutic vaccines. They can accommodate and stably maintain a large genomic payload of foreign inserts. Their limited replication in human cells provides an excellent safety profile, but it concomitantly necessitates higher doses of infectious particles for full therapeutic efficacy. AREAS COVERED: We review recent advances in bioprocesses for the pharmaceutical production of poxvirus-based vectors, focusing mainly on the vaccinia virus and the Orf virus. These include upstream processing using highly permissive cell substrates, optimized feeding strategies, and a virus phenotype that facilitates downstream processing. The study explores ongoing challenges and identifies strategies to adapt the downstream process to intensified upstream processes in order to achieve an economic end-to-end production. EXPERT OPINION: For notably increased virus yields of up to 2 log after amplification, we propose to replace classic adsorption chromatography by a collective and continuous purification platform for separating the virus from process-related impurities. Filtration operations facilitate process scalability while reducing volumes, which is beneficial for a flow-through polishing to meet pharmaceutical quality attributes. Combined with artificial intelligence modeling, these advancements alleviate financial pressures on healthcare systems and accelerate the production of novel vaccine candidates for clinical use.

Humans↗
PubMed2026

Polymerase-inhibitor drug synergy and mutational signatures in different epithelial cell models of RSVA and hPIV3 infection.

Despite the huge global health burden presented by respiratory viruses, effective broad-spectrum antiviral therapeutic options remain limited. Here we evaluated the antiviral activity of four RNA-dependent RNA polymerase (RdRp) inhibitors, remdesivir, ribavirin, favipiravir, and molnupiravir, as monotherapy or dual-drug combinations against respiratory syncytial virus (subtype A, RSVA) and human parainfluenza (serotype 3, hPIV3) using epithelial cell lines and primary human airway culture models. Remdesivir showed the greatest potency across both viruses, while ribavirin and favipiravir also demonstrated inhibition. Molnupiravir was active against RSVA but not hPIV3. Several dual-drug combinations, including remdesivir-favipiravir, remdesivir-molnupiravir and favipiravir-molnupiravir, produced marked synergy against RSVA, and more limited synergy for hPIV3. Antiviral efficacy was validated in primary airway epithelial cultures, where effective concentrations preserved epithelial integrity and attenuated viral disruption of ciliary function. Across both viruses, increasing antiviral exposure was associated with dose-dependent signature mutagenesis. Antivirals induced significantly higher RSVA mutation burden in the primary airway model. These findings highlight the therapeutic potential of RdRp inhibitor combinations for RSVA and hPIV3, provide mechanistic insight through antiviral-related mutational signatures, and demonstrate advantages of the primary human airway culture model for development of effective multi-drug regimens and broad-spectrum antiviral preparedness.

Journal Article↗
PubMed1975

Evaluation of a bovine viral diarrhea vaccine produced in a porcine kidney cell line.

An attenuated bovine viral diarrhea (BVD) live-virus vaccine, produced in a continuous porcine cell line, evoked an immune response which produced a protective level of serum antibodies in vaccinated cattle. Post-vaccinal reactions to the vaccinal virus were not observed in cattle vaccinated at 5 feedlots or in cattle vaccinated in experimental tests. The vaccinal virus did not produce demonstrable viremia or detectable excretion of virus from the respiratory or digestive tracts. Leukopenia or abnormality in differential leukocyte values did not occur as with virulent BVD viral infection. Transmission of vaccinal virus from vaccinated cattle to susceptible controls did not occur under conditions in which vaccinated and nonvaccinated cattle were in constant contact for 28 days.

Animals↗
PubMed2026

RNA structures regulate norovirus life cycle and enable rational attenuation in vivo.

Viral genomes encode regulatory RNA structures that orchestrate key steps of viral replication and gene expression. Although these structures are increasingly recognized as critical regulators of viral function, their systematic characterization in an infection context and roles in regulating viral fitness and immune recognition in vivo remain limited. Here, we systematically map and functionally interrogate structured RNA elements across the murine norovirus genome using orthogonal in-cell chemical probing, revealing conserved motifs that regulate viral function. Targeted disruption of specific structural elements reduces viral replication in cell culture, modulates translation in cis, and decreases viral RNA levels in animal infection models. These findings enabled the rational design of a genetically stable, attenuated virus that elicits protective immunity and limits viral replication upon secondary challenge. Together, this work uncovers essential roles for RNA structure in norovirus biology and establishes a generalizable framework for RNA structure-guided design of antiviral vaccines and therapeutics.

RNA structure↗
PubMedDate not supplied

[Interfering and interferonogenic activity of attenuated and original para-influenza viral strains].

A higher interfering activity of attenuated (vaccine) strains of parainfluenza virus types 1, 2 and 3 which had undergone a long-term adaptation to cell cultures as compared to the original viruses was established. The interferon-inducing activity of vaccine parainfluenza virus types 2 and 3 was also higher than that of the original viruses. The high interfering and interferon-inducing activity of attenuated parainfluenza virus strains of type 2 and 3 correlated with reduced virulence of these variants for man. These tests may be used for the assessment of virulence of parainfluenza virus strains type 2 and 3 in the laboratory.

Cells, Cultured↗
PubMed1977

Analysis of VSV mutant with attenuated cytopathogenicity: mutation in viral function, P, for inhibition of protein synthesis.

T1026, a ts mutant of VSV which is much less cytopathogenic than its parent, HR, and which can establish persistent infection under certain conditions, is a double mutant. In addition to its ts mutation in the virion RNA polymerase, T1026 has a second non-ts mutation in a viral function termed "P". This function is responsible for the inhibition of total protein synthesis in infected cells and acts chiefly at the level of translational initiation. In some cell systems, the inhibition of protein synthesis produced by P appears to be selective for cellular protein synthesis, whereas in other cell systems, both cellular and viral protein synthesis are inhibited. T1026 and its ts revertants are phenotypically P- -that is, cells infected with them show total protein synthesis rates equal to or greater than uninfected cells, while synthesizing viral proteins at the same or even greater rates than HR-infected cells. The P- mutation is correlated with failure to increase plaque size after 2-3 days of incubation. Since viral mutants obtained from persistently infected cultures in a variety of systems appear to be double mutants with a ts mutation in the virion RNA polymerase and a small plaque marker, we suggest that T1026 could represent a model for such mutants.

Animals↗
PubMed1979

Immune response to virus-infection-associated (VIA) antigen in cattle repeatedly vaccinated with foot-and-mouth disease virus inactivated by formalin or acetylethyleneimine.

The results of experiments to investigate antibody to 'virus infection associated' (VIA) antigen in cattle repeatedly vaccinated with formalin- or acetylethyleneimine- (AEI) inactivated foot-and-mouth disease (FMD) vaccines under laboratory conditions are reported. Results are also presented from some vaccinated animals subsequently exposed to FMD infection. Antibody against VIA was not detected before and after the first vaccination with formalin or AEI-inactivated vaccine but did develop in all animals after the second formalin vaccination and persisted throughout the experiment. After the second AEI vaccination, 4 of 12 animals developed antibody which persisted for at least 37 days. This transient response in some cattle was repeated after successive vaccinations but, in general, more animals responded as the number of vaccinations increased. After exposure to infection a transient VIA antibody response was occasionally observed in immune AEI-vaccinated animals. Some immune repeatedly AEI-vaccinated cattle did not develop detectable VIA antibody after challenge despite the persistence of virus in oesophageal-pharyngeal (O/P) fluid. The presence of antibody to VIA antigen is not conclusive proof that vaccinated animals have been exposed to infection and field data must be interpreted with caution.

Animals↗