FAIR TAXATION UNDER THE GLOBAL ANTI-BASE EROSION RULES?

In 2021 the OECD launched the Global Minimum Company Tax to implement the Action 1 of the BEPS Project. This instrument has seen as a good mechanism to prevent company avoiding taxes at the global level and to stop existence of the harmful tax regimes worldwide, as well as a good mechanism to achieve fair taxation in the era of global digitalization. However, the broke-out of the COVID-19 pandemic and, consequently, the close of the national borders, then armed conflict between Russia and Ukraine, boost financial crisis and the crises in almost all social and industrial spheres at the global level. Such unwilling trend, between all, has influenced behavior of the companies and the initial optimism of the OECD and other international organizations that the global minimum company tax, at the very end, would end existence of the harmful tax regimes, tax avoidance and unfair taxation, dropped significantly. Therefore, at the very end of the 2022 and the beginning of the 2023, the OECD launched consultation document on tax certainty in the application of the Pillar Two of the global minimum tax known as a GloBE (Global Anti-Base Erosion) Model Rules. This paper deals with mentioned issue and actual problems that the application of the GLoBE rules is faced with.

The immunopathology of COVID-19 placentitis: A multi-omic spatial approach

Problem: COVID-19 placentitis is a rare complication of maternal SARS-CoV-2 respiratory infection associated with serious adverse obstetric outcomes, including intra-uterine death. The precise role of SARS-CoV-2 in COVID-19 placentitis is uncertain, as trophoblast infection is only observed in around one-half of the affected placenta. Method of Study: Through multi-omic spatial profiling, including Nanostring GeoMX digital spatial profiling and Lunaphore COMET multiplex IHC, we provide a deep characterization of the immunopathology of placentitis from obstetrically complicated maternal COVID-19 infection. Result(s):We show that SARS-CoV-2 infection of placental trophoblasts is associated with a distinct innate and adaptive immune cell infiltrate, florid cytokine expression and upregulation of viral restriction factors. Quantitative spatial analyses reveal a unique microenvironment surrounding virus-infected trophoblasts characterizedd by multiple immune evasion mechanisms, including immune checkpoint expression, cytotoxic T-cell exclusion, and interferon blunting. Placental viral loads inversely correlated with the duration of maternal infection consistent with progressive virus clearance, potentially explaining the absence of virus in some cases. Conclusion(s): Our results demonstrate a central role for placental SARS-CoV-2 infection in driving the unique immunopathology of COVID-19 placentitis.

SARS-CoV-2 within-host diversity of human hosts and its implications for viral immune evasion.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continuously evolving, bringing great challenges to the control of the virus. In the present study, we investigated the characteristics of SARS-CoV-2 within-host diversity of human hosts and its implications for immune evasion using about 2,00,000 high-depth next-generation genome sequencing data of SARS-CoV-2. A total of 44% of the samples showed within-host variations (iSNVs), and the average number of iSNVs in the samples with iSNV was 1.90. C-to-U is the dominant substitution pattern for iSNVs. C-to-U/G-to-A and A-to-G/U-to-C preferentially occur in 5'-CG-3' and 5'-AU-3' motifs, respectively. In addition, we found that SARS-CoV-2 within-host variations are under negative selection. About 15.6% iSNVs had an impact on the content of the CpG dinucleotide (CpG) in SARS-CoV-2 genomes. We detected signatures of faster loss of CpG-gaining iSNVs, possibly resulting from zinc-finger antiviral protein-mediated antiviral activities targeting CpG, which could be the major reason for CpG depletion in SARS-CoV-2 consensus genomes. The non-synonymous iSNVs in the S gene can largely alter the S protein's antigenic features, and many of these iSNVs are distributed in the amino-terminal domain (NTD) and receptor-binding domain (RBD). These results suggest that SARS-CoV-2 interacts actively with human hosts and attempts to take different evolutionary strategies to escape human innate and adaptive immunity. These new findings further deepen and widen our understanding of the within-host evolutionary features of SARS-CoV-2.IMPORTANCESevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of the coronavirus disease 2019, has evolved rapidly since it was discovered. Recent studies have pointed out that some mutations in the SARS-CoV-2 S protein could confer SARS-CoV-2 the ability to evade the human adaptive immune system. In addition, it is observed that the content of the CpG dinucleotide in SARS-CoV-2 genome sequences has decreased over time, reflecting the adaptation to the human host. The significance of our research is revealing the characteristics of SARS-CoV-2 within-host diversity of human hosts, identifying the causes of CpG depletion in SARS-CoV-2 consensus genomes, and exploring the potential impacts of non-synonymous within-host variations in the S gene on immune escape, which could further deepen and widen our understanding of the evolutionary features of SARS-CoV-2.

Poor neutralizing antibody responses against SARS-CoV-2 Omicron BQ.1.1 and XBB in Norway in October 2022.

New immune evasive variants of SARS-CoV-2 continue to emerge, potentially causing new waves of covid-19 disease. Here, we evaluate levels of neutralizing antibodies against isolates of Omicron variants, including BQ.1.1 and XBB, in sera harvested 3-4 weeks after vaccination or breakthrough infections. In addition, we evaluate neutralizing antibodies in 32 sera from October 2022, to evaluate immunity in Norwegian donors prior to the winter season. Most serum samples harvested in October 2022 had low levels of neutralizing antibodies against BQ.1.1 and especially XBB, explaining why these variants and their descendants have dominated in Norway during the 2022 and 2023 winter season.

Reprogramming viral immune evasion for a rational design of next-generation vaccines for RNA viruses.

Type I interferons (IFNs-α/ß) are antiviral cytokines that constitute the innate immunity of hosts to fight against viral infections. Recent studies, however, have revealed the pleiotropic functions of IFNs, in addition to their antiviral activities, for the priming of activation and maturation of adaptive immunity. In turn, many viruses have developed various strategies to counteract the IFN response and to evade the host immune system for their benefits. The inefficient innate immunity and delayed adaptive response fail to clear of invading viruses and negatively affect the efficacy of vaccines. A better understanding of evasion strategies will provide opportunities to revert the viral IFN antagonism. Furthermore, IFN antagonism-deficient viruses can be generated by reverse genetics technology. Such viruses can potentially serve as next-generation vaccines that can induce effective and broad-spectrum responses for both innate and adaptive immunities for various pathogens. This review describes the recent advances in developing IFN antagonism-deficient viruses, their immune evasion and attenuated phenotypes in natural host animal species, and future potential as veterinary vaccines.

Innate and adaptive immunity to SARS-CoV-2 and predisposing factors.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), has affected all countries worldwide. Although some symptoms are relatively mild, others are still associated with severe and even fatal clinical outcomes. Innate and adaptive immunity are important for the control of SARS-CoV-2 infections, whereas a comprehensive characterization of the innate and adaptive immune response to COVID-19 is still lacking and the mechanisms underlying immune pathogenesis and host predisposing factors are still a matter of scientific debate. Here, the specific functions and kinetics of innate and adaptive immunity involved in SARS-CoV-2 recognition and resultant pathogenesis are discussed, as well as their immune memory for vaccinations, viral-mediated immune evasion, and the current and future immunotherapeutic agents. We also highlight host factors that contribute to infection, which may deepen the understanding of viral pathogenesis and help identify targeted therapies that attenuate severe disease and infection.

SARS-CoV-2 NSP13 interacts with host IRF3, blocking antiviral immune responses.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses an unprecedented threat to human health since late 2019. Notably, the progression of the disease is associated with impaired antiviral interferon (IFN) responses. Although multiple viral proteins were identified as potential IFN antagonists, the underlying molecular mechanisms remain to be fully elucidated. In this study, we firstly demonstrate that SARS-CoV-2 NSP13 protein robustly antagonizes IFN response induced by the constitutively active form of transcription factor IRF3 (IRF3/5D). This induction of IFN response by IRF3/5D is independent of the upstream kinase, TBK1, a previously reported NSP13 target, thus indicating that NSP13 can act at the level of IRF3 to antagonize IFN production. Consistently, NSP13 exhibits a specific, TBK1-independent interaction with IRF3, which, moreover, is much stronger than that of NSP13 with TBK1. Furthermore, the NSP13-IRF3 interaction was shown to occur between the NSP13 1B domain and IRF3 IRF association domain (IAD). In agreement with the strong targeting of IRF3 by NSP13, we then found that NSP13 blocks IRF3-directed signal transduction and antiviral gene expression, counteracting IRF3-driven anti-SARS-CoV-2 activity. These data suggest that IRF3 is likely to be a major target of NSP13 in antagonizing antiviral IFN responses and provide new insights into the SARS-CoV-2-host interactions that lead to viral immune evasion.

SARS-CoV-2 Evasion of the Interferon System: Can We Restore Its Effectiveness?

Type I and III Interferons (IFNs) are the first lines of defense in microbial infections. They critically block early animal virus infection, replication, spread, and tropism to promote the adaptive immune response. Type I IFNs induce a systemic response that impacts nearly every cell in the host, while type III IFNs' susceptibility is restricted to anatomic barriers and selected immune cells. Both IFN types are critical cytokines for the antiviral response against epithelium-tropic viruses being effectors of innate immunity and regulators of the development of the adaptive immune response. Indeed, the innate antiviral immune response is essential to limit virus replication at the early stages of infection, thus reducing viral spread and pathogenesis. However, many animal viruses have evolved strategies to evade the antiviral immune response. The Coronaviridae are viruses with the largest genome among the RNA viruses. Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) caused the coronavirus disease 2019 (COVID-19) pandemic. The virus has evolved numerous strategies to contrast the IFN system immunity. We intend to describe the virus-mediated evasion of the IFN responses by going through the main phases: First, the molecular mechanisms involved; second, the role of the genetic background of IFN production during SARS-CoV-2 infection; and third, the potential novel approaches to contrast viral pathogenesis by restoring endogenous type I and III IFNs production and sensitivity at the sites of infection.

Molecular mechanisms and cellular functions of liquid-liquid phase separation during antiviral immune responses.

Spatiotemporal separation of cellular components is vital to ensure biochemical processes. Membrane-bound organelles such as mitochondria and nuclei play a major role in isolating intracellular components, while membraneless organelles (MLOs) are accumulatively uncovered via liquid-liquid phase separation (LLPS) to mediate cellular spatiotemporal organization. MLOs orchestrate various key cellular processes, including protein localization, supramolecular assembly, gene expression, and signal transduction. During viral infection, LLPS not only participates in viral replication but also contributes to host antiviral immune responses. Therefore, a more comprehensive understanding of the roles of LLPS in virus infection may open up new avenues for treating viral infectious diseases. In this review, we focus on the antiviral defense mechanisms of LLPS in innate immunity and discuss the involvement of LLPS during viral replication and immune evasion escape, as well as the strategy of targeting LLPS to treat viral infectious diseases.

A Methodical Review on Omicron -a New Variant as a Drug Developer

In mid-November 2021, the new OMICRON variety was first discovered in South Africa. As of today, the OMICRON version already appeared on December 15, 2021. Around 77 countries are affected, with the bulk of cases originating in the United States, India, the United Kingdom, and South Africa. OMICRON-positive instances were also reported. The first mortality associated with the novel COVID-19 mutation was reported in the United Kingdom. Recently, a sister variant of OMICRON, 21L or BA.2, has also been discovered. Due to its enormously high number of mutations, viewed enhancement in immune evasion and transmissibility, OMICRON was developed as a new variant of concern (VOC) by the WHO on 26 November 2021. On a global pandemic scale, positive selection of SARSCoV-2 mutations appears to have begun in late 2020. Since then, the virus has been evolving on two fronts: immune evasion and enhanced transmissibility, as expressed by Delta. This review elaborates the effects of drugs in the management of OMICRON.Copyright © 2023 Society of Pharmaceutical Sciences and Research. All rights reserved.

SARS-CoV-2 Delta variant genomic variation associated with breakthrough infection in Northern California: A retrospective cohort study.

BACKGROUND: The association between SARS-CoV-2 genomic variation and breakthrough infection is not well-defined among persons with Delta variant SARS-CoV-2 infection. METHODS: In a retrospective cohort we assessed whether individual non-lineage defining mutations and overall genomic variation (including low frequency alleles) were associated with breakthrough infection defined as SARS-CoV-2 infection after COVID-19 primary vaccine series. We identified all non-synonymous single nucleotide polymorphisms, insertions and deletions in SARS-CoV-2 genomes with ≥5% allelic frequency and population frequency of ≥5% and ≤95%. Using Poisson regression, we assessed the association with breakthrough infection for each individual mutation and a viral genomic risk score. RESULTS: Thirty-six mutations met our inclusion criteria. Among 12,744 persons infected with Delta variant SARS-CoV-2, 5,949 (47%) were vaccinated and 6,795 (53%) were unvaccinated. Viruses with a viral genomic risk score in the highest quintile were 9% more likely to be associated with breakthrough infection than viruses in the lowest quintile, but including the risk score improved overall predictive model performance (measured by c-statistic) by only +0.0006. CONCLUSIONS: Genomic variation within SARS-CoV-2 Delta variant was weakly associated with breakthrough infection, however several potential non-lineage defining mutations were identified that might contribute to immune evasion by SARS-CoV-2.

Navigating through administrative data to evaluate realworld effectiveness of COVID-19 vaccines in Malaysia: The RECoVaM experience

Real-world effectiveness studies are important for monitoring the performance of COVID-19 vaccination strategies and informing COVID-19 prevention and control policies. The Real-World Effectiveness of COVID-19 Vaccine under the Malaysian National COVID-19 Immunisation Program (RECoVaM) analysed effectiveness of a range of homologous primary, as well as heterologous and homologous booster COVID-19 vaccines, which comprised of BNT162b2 (mRNA), CoronaVac (inactivated) and AZD1222 (viral vectored), against SARS-CoV-2 infection and severe COVID-19. Nationally comprehensive administrative data at both individual- and aggregate-levels were consolidated for each analysis. These were the Malaysia national COVID-19 vaccinations register (MyVAS), COVID-19 cases line listing, intensive care unit (ICU) admissions register, deaths line listing, supervised test registry (SIMKA), and the MySejahtera check-ins-based automated contact tracing registry (AutoTrace). RECoVaM adopted several observational study designs. Exposure periods were carefully calibrated to account for the structure of Malaysia's COVID-19 data, and epidemiological context, to estimate vaccine effectiveness. Importantly, RECoVaM also compared effectiveness measures during both the Delta-dominant, and Omicron-dominant periods. Effectiveness estimates for primary vaccinations showed a reduction in risk of SARS-CoV-2 infections by 87 - 91%, and symptomatic infections by 85 - 89%, as well as ICU admission by 82 - 84% among COVID-19 cases, and death by 86 - 88% among COVID-19 cases. All vaccine platforms were effective in reducing risk against ICU admission and death. Subsequently, significant waning of protection was demonstrated against COVID-19 infection among BNT162b2 (90.8 to 79.3%) and CoronaVac (74.5 to 30.4%) recipients 3 to 5 months post-primary vaccinations. Protection against ICU admission for CoronaVac waned (56.0 to 28.7%) and was more substantial among the elderly (aged 60 years and above). The estimates of marginal Vaccine Effectiveness (mVE) for boosters showed that recipients of booster doses were at least 90% less likely to be infected with COVID-19 relative to primary BNT162b2 vaccination during the Delta-dominant period. In both Delta and Omicron-dominant periods, homologous BNT162b2 boosting offered the highest protection against infection relative to primary BNT162b2 vaccination. This is followed by heterologous boosting with either AZD1222 or BNT162b2 for recipients primed with CoronaVac or AZD1222, and finally homologous boosting with AZD1222 and CoronaVac. The mVE estimates for all booster combinations in the Omicrondominant period was about half that of Delta. Vaccination with a primary COVID-19 vaccines were effective in reducing COVID-19 infection but wanes after 3-5 months. Additional booster doses were more effective than primary series alone in preventing COVID-19 infection but demonstrated an interplay of immune evasion during the Omicron-dominant period. Homologous BNT162b2 boosting aside, and heterologous boosting appeared to be more protective than homologous boosting. Although vaccination is still protective against severe infection, ongoing community transmission could facilitate viral mutation. Next generation, multivalent vaccines aimed at stemming transmission, are warranted.

Impact of Direct Taxation on Economic Growth: Empirical Evidence Based on Panel Data Regression Analysis at the Level of Eu Countries

Through fiscal policy, the government can influence businesses and individuals in order to regulate their behaviour. The research used panel data from all 27 EU countries covering the period 2008–2020 to investigate the impact of direct taxation on economic growth at the level of two main clusters of countries concerning fiscal efficiency. Therefore, the analysis employed cluster methods to classify the main EU countries in both groups of countries with a high level of fiscal efficiency and those with a rather limited level of fiscal efficiency. The study employs fixed effect models and dynamic GMM methods to investigate the effect of direct taxation components (personal and corporate income taxes) on economic growth. The analysis also considers the informal economy's role in relation to the official economy. The empirical results revealed that corporate income taxes significantly negatively impact economic growth for both clusters of high- and limited fiscal efficiency countries. Additionally, personal income tax was associated with lower economic growth for countries in the limited fiscal efficiency group. Thus, from the perspective of policymakers, lowering direct taxation can increase disposable income, stimulate consumption and economic growth, encourage investment leading to job creation, increase competitiveness, and reduce tax evasion and avoidance, thereby leading to a more efficient tax system.

Impaired potency of neutralizing antibodies against cell-cell fusion mediated by SARS-CoV-2.

The SARS-CoV-2 Omicron subvariants have dominated the pandemic due to their high transmissibility and immune evasion conferred by the spike mutations. The Omicron subvariants can spread by cell-free virus infection and cell-cell fusion, the latter of which is more effective but has not been extensively investigated. In this study, we developed a simple and high-throughput assay that provides a rapid readout to quantify cell-cell fusion mediated by the SARS-CoV-2 spike proteins without using live or pseudotyped virus. This assay can be used to identify variants of concern and to screen for prophylactic and therapeutic agents. We further evaluated a panel of monoclonal antibodies (mAbs) and vaccinee sera against D614G and Omicron subvariants, finding that cell-cell fusion is substantially more resistant to mAb and serum inhibition than cell-free virus infection. Such results have important implications for the development of vaccines and antiviral antibody drugs against cell-cell fusion induced by SARS-CoV-2 spikes.

Enhanced evasion of neutralizing antibody response by Omicron XBB.1.5, CH.1.1, and CA.3.1 variants.

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.

Enhanced inhibition of MHC-I expression by SARS-CoV-2 Omicron subvariants.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) possess mutations that confer resistance to neutralizing antibodies within the Spike protein and are associated with breakthrough infection and reinfection. By contrast, less is known about the escape from CD8+ T cell-mediated immunity by VOC. Here, we demonstrated that all SARS-CoV-2 VOCs possess the ability to suppress major histocompatibility complex class I (MHC-I) expression. We identified several viral genes that contribute to the suppression of MHC I expression. Notably, MHC-I upregulation was strongly inhibited after SARS-CoV-2 but not influenza virus infection in vivo. While earlier VOCs possess similar capacity as the ancestral strain to suppress MHC-I, the Omicron subvariants exhibited a greater ability to suppress surface MHC-I expression. We identified a common mutation in the E protein of Omicron that further suppressed MHC-I expression. Collectively, our data suggest that in addition to escaping from neutralizing antibodies, the success of Omicron subvariants to cause breakthrough infection and reinfection may in part be due to its optimized evasion from T cell recognition.

Vaccines Alone Cannot Slow the Evolution of SARS-CoV-2.

The rapid emergence of immune-evading viral variants of SARS-CoV-2 calls into question the practicality of a vaccine-only public-health strategy for managing the ongoing COVID-19 pandemic. It has been suggested that widespread vaccination is necessary to prevent the emergence of future immune-evading mutants. Here, we examined that proposition using stochastic computational models of viral transmission and mutation. Specifically, we looked at the likelihood of emergence of immune escape variants requiring multiple mutations and the impact of vaccination on this process. Our results suggest that the transmission rate of intermediate SARS-CoV-2 mutants will impact the rate at which novel immune-evading variants appear. While vaccination can lower the rate at which new variants appear, other interventions that reduce transmission can also have the same effect. Crucially, relying solely on widespread and repeated vaccination (vaccinating the entire population multiple times a year) is not sufficient to prevent the emergence of novel immune-evading strains, if transmission rates remain high within the population. Thus, vaccines alone are incapable of slowing the pace of evolution of immune evasion, and vaccinal protection against severe and fatal outcomes for COVID-19 patients is therefore not assured.

SARS-CoV-2 Omicron Variant in Medicinal Chemistry Research.

The Coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and threatens public health and safety. Nowadays, modern society has faced a new challenging problem, the emergence of novel SARS-CoV-2 variants of concern (VOCs). In this context, the Omicron (B.1.1.529) variant, having more than 60 mutations when compared to its ancestral wild-type virus, has infected many individuals around the world. It is rapidly spread person-to-person due to its increased transmissibility. Additionally, it was demonstrated that this newest variant and its subvariants have the capability of evading the host immune system, being resistant to neutralizing antibodies. Moreover, it has been proven to be resistant to monoclonal antibodies and several different vaccines. This ability is associated with a huge number of mutations associated with its spike (S) glycoprotein, which presents at least 15 mutations. These mutations are able to modify the way how this virus interacts with the host angiotensin-converting enzyme 2 (ACE2), increasing its infectivity and making the therapeutic alternatives more ineffective. Concerning its chymotrypsin-like picornavirus 3C-like protease (3CLpro) and RNA-dependent RNA polymerase (RdRp), it has been seen that some compounds can be active against different SARS-CoV-2 variants, in a similar mode than its wild-type precursor. This broad spectrum of action for some drugs could be attributed to the fact that the currently identified mutations found in 3CLpro and RNA proteins being localized near the catalytic binding site, conserving their activities. Herein this review, we provide a great and unprecedented compilation of all identified and/or repurposed compounds/drugs against this threatening variant, Omicron. The main targets for those compounds are the protein-protein interface (PPI) of S protein with ACE2, 3CLpro, RdRp, and Nucleocapsid (N) protein. Some of these studies have presented only in silico data, having a lack of experimental results to prove their findings. However, these should be considered here since other research teams can use their observations to design and investigate new potential agents. Finally, we believe that our review will contribute to several studies that are in progress worldwide, compiling several interesting aspects about VOCs associated with SARS-CoV2, as well as describing the results for different chemical classes of compounds that could be promising as prototypes for designing new and more effective antiviral agents.

SARS-CoV-2 ORF8: A Rapidly Evolving Immune and Viral Modulator in COVID-19.

The COVID-19 pandemic has resulted in upwards of 6.8 million deaths over the past three years, and the frequent emergence of variants continues to strain global health. Although vaccines have greatly helped mitigate disease severity, SARS-CoV-2 is likely to remain endemic, making it critical to understand its viral mechanisms contributing to pathogenesis and discover new antiviral therapeutics. To efficiently infect, this virus uses a diverse set of strategies to evade host immunity, accounting for its high pathogenicity and rapid spread throughout the COVID-19 pandemic. Behind some of these critical host evasion strategies is the accessory protein Open Reading Frame 8 (ORF8), which has gained recognition in SARS-CoV-2 pathogenesis due to its hypervariability, secretory property, and unique structure. This review discusses the current knowledge on SARS-CoV-2 ORF8 and proposes actualized functional models describing its pivotal roles in both viral replication and immune evasion. A better understanding of ORF8's interactions with host and viral factors is expected to reveal essential pathogenic strategies utilized by SARS-CoV-2 and inspire the development of novel therapeutics to improve COVID-19 disease outcomes.

Oncolytic Rodent Protoparvoviruses Evade a TLR- and RLR-Independent Antiviral Response in Transformed Cells.

The oncolytic rodent protoparvoviruses (PVs) minute virus of mice (MVMp) and H-1 parvovirus (H-1PV) are promising cancer viro-immunotherapy candidates capable of both exhibiting direct oncolytic activities and inducing anticancer immune responses (AIRs). Type-I interferon (IFN) production is instrumental for the activation of an efficient AIR. The present study aims at characterizing the molecular mechanisms underlying PV modulation of IFN induction in host cells. MVMp and H-1PV triggered IFN production in semi-permissive normal mouse embryonic fibroblasts (MEFs) and human peripheral blood mononuclear cells (PBMCs), but not in permissive transformed/tumor cells. IFN production triggered by MVMp in primary MEFs required PV replication and was independent of the pattern recognition receptors (PRRs) Toll-like (TLR) and RIG-like (RLR) receptors. PV infection of (semi-)permissive cells, whether transformed or not, led to nuclear translocation of the transcription factors NFĸB and IRF3, hallmarks of PRR signaling activation. Further evidence showed that PV replication in (semi-)permissive cells resulted in nuclear accumulation of dsRNAs capable of activating mitochondrial antiviral signaling (MAVS)-dependent cytosolic RLR signaling upon transfection into naïve cells. This PRR signaling was aborted in PV-infected neoplastic cells, in which no IFN production was detected. Furthermore, MEF immortalization was sufficient to strongly reduce PV-induced IFN production. Pre-infection of transformed/tumor but not of normal cells with MVMp or H-1PV prevented IFN production by classical RLR ligands. Altogether, our data indicate that natural rodent PVs regulate the antiviral innate immune machinery in infected host cells through a complex mechanism. In particular, while rodent PV replication in (semi-)permissive cells engages a TLR-/RLR-independent PRR pathway, in transformed/tumor cells this process is arrested prior to IFN production. This virus-triggered evasion mechanism involves a viral factor(s), which exert(s) an inhibitory action on IFN production, particularly in transformed/tumor cells. These findings pave the way for the development of second-generation PVs that are defective in this evasion mechanism and therefore endowed with increased immunostimulatory potential through their ability to induce IFN production in infected tumor cells.