The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants in different continents is causing a major concern in human global health. These variants have in common a ...higher transmissibility, becoming dominant within populations in a short time, and an accumulation of a high number of mutations in the spike (S) protein, especially within the amino terminal domain (NTD) and the receptor binding domain (RBD). These mutations have direct implications on virus infection rates through higher affinity of S RBD for the cellular angiotensin-converting enzyme-2 (ACE-2) receptor. There are also signs of enhanced virulence, re-infection frequency, and increased resistance to the action of monoclonal and polyclonal antibodies from convalescence sera and in vaccinated individuals in regions where the variants spread dominantly. In this review, we describe the different SARS-CoV-2 variants that have thus far been identified in various parts of the world with mutational changes and biological properties as well as their impact in medical countermeasures and human health.
The goal of successful anti-tumoural immunity is the development of long-term protective immunity to prevent relapse. Infiltration of tumours with CD8
T cells with a resident memory (Trm) phenotype ...correlates with improved survival. However, the interplay of circulating CD8
T cells and Trm cells remains poorly explored in tumour immunity. Using different vaccination strategies that fine-tune the generation of Trm cells or circulating memory T cells, here we show that, while both subsets are sufficient for anti-tumour immunity, the presence of Trm cells improves anti-tumour efficacy. Transferred central memory T cells (Tcm) generate Trm cells following viral infection or tumour challenge. Anti-PD-1 treatment promotes infiltration of transferred Tcm cells within tumours, improving anti-tumour immunity. Moreover, Batf3-dependent dendritic cells are essential for reactivation of circulating memory anti-tumour response. Our findings show the plasticity, collaboration and requirements for reactivation of memory CD8
T cells subsets needed for optimal tumour vaccination and immunotherapy.
Obesity is the result of interactions between genes and environmental factors. Since monogenic etiology is only known in some obesity-related genes, a genetic risk score (GRS) could be useful to ...determine the genetic predisposition to obesity. Therefore, the aim of our study was to build a GRS able to predict genetic predisposition to overweight and obesity in European adolescents. A total of 1069 adolescents (51.3% female), aged 11-19 years participating in the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) cross-sectional study were genotyped. The sample was divided in non-overweight (non-OW) and overweight/obesity (OW/OB). From 611 single nucleotide polymorphisms (SNP) available, a first screening of 104 SNPs univariately associated with obesity (p < 0.20) was established selecting 21 significant SNPs (p < 0.05) in the multivariate model. Unweighted GRS (uGRS) was calculated by summing the number of risk alleles and weighted GRS (wGRS) by multiplying the risk alleles to each estimated coefficient. The area under curve (AUC) was calculated in uGRS (0.723) and wGRS (0.734) using tenfold internal cross-validation. Both uGRS and wGRS were significantly associated with body mass index (BMI) (p < .001). Both GRSs could potentially be considered as useful genetic tools to evaluate individual's predisposition to overweight/obesity in European adolescents.
Previous studies suggested that poxvirus-based vaccines might be instrumental in the therapeutic HIV field. A phase I clinical trial was conducted in HIV-1-infected patients on highly active ...antiretroviral therapy (HAART), with CD4 T cell counts above 450 cells/mm3 and undetectable viremia. Thirty participants were randomized (2:1) to receive either 3 intramuscular injections of MVA-B vaccine (coding for clade B HIV-1 Env, Gag, Pol and Nef antigens) or placebo, followed by interruption of HAART.
The magnitude, breadth, quality and phenotype of the HIV-1-specific T cell response were assayed by intracellular cytokine staining (ICS) in 22 volunteers pre- and post-vaccination.
MVA-B vaccine induced newly detected HIV-1-specific CD4 T cell responses and expanded pre-existing responses (mostly against Gag, Pol and Nef antigens) that were high in magnitude, broadly directed and showed an enhanced polyfunctionality with a T effector memory (TEM) phenotype, while maintaining the magnitude and quality of the pre-existing HIV-1-specific CD8 T cell responses. In addition, vaccination also triggered preferential CD8+ T cell polyfunctional responses to the MVA vector antigens that increase in magnitude after two and three booster doses.
MVA-B vaccination represents a feasible strategy to improve T cell responses in individuals with pre-existing HIV-1-specific immunity.
ClinicalTrials.gov NCT01571466.
Vaccinia virus (VACV), a prototype member of the poxvirus family, has been used from the early times after interferons (IFN) were discovered, as a model virus cell system to analyze the mode of ...action of IFN. This large DNA-containing virus (around 200 kb) replicates entirely in the cytoplasm of the cell, taking rapidly over the host cell machinery for virus multiplication. In the presence of IFN, this virus exhibits sensitivity or resistance depending on the virus-host model. With the discovery of IFN-induced enzymes, the sensitivity of VACV to IFN was correlated with dsRNA activation of the protein kinase PKR and 2'-5'-OAS/RNaseL systems leading to a translational block by the phosphorylation of the eIF2 alpha factor and RNA breakdown. Following sequencing of the VACV genome and generation of deletion mutants, the resistance phenomenon to IFN was shown to be exerted through inhibition of multiple pathways. This review analyzes current knowledge on the VACV genes encoding proteins acting as decoy receptors to block the activity of type I and type II IFNs, targeting cytokines and chemokines, and antagonizing intracellular signaling pathways (pattern recognition receptors PRRs signaling). The molecular dissection of how VACV prevents the IFN response is providing important insights on our understanding of antiviral action and immune surveillance.
Studies are needed to identify useful biomarkers to assess the severity and prognosis of COVID‐19 disease, caused by severe acute respiratory syndrome coronavirus (SARS‐CoV‐2) virus. Here, we examine ...the levels of various plasma species of the SARS‐CoV‐2 host receptor, the angiotensin‐converting enzyme 2 (ACE2), in patients at different phases of the infection. Human plasma ACE2 species were characterized by immunoprecipitation and western blotting employing antibodies against the ectodomain and the C‐terminal domain, using a recombinant human ACE2 protein as control. In addition, changes in the cleaved and full‐length ACE2 species were also examined in serum samples derived from humanized K18‐hACE2 mice challenged with a lethal dose of SARS‐CoV‐2. ACE2 immunoreactivity was present in human plasma as several molecular mass species that probably comprise truncated (70 and 75 kDa) and full‐length forms (95, 100, 130, and 170 kDa). COVID‐19 patients in the acute phase of infection (n = 46) had significantly decreased levels of ACE2 full‐length species, while a truncated 70‐kDa form was marginally higher compared with non‐disease controls (n = 26). Levels of ACE2 full‐length species were in the normal range in patients after a recovery period with an interval of 58‐70 days (n = 29), while the 70‐kDa species decreased. Levels of the truncated ACE2 species served to discriminate between individuals infected by SARS‐CoV‐2 and those infected with influenza A virus (n = 17). In conclusion, specific plasma ACE2 species are altered in patients with COVID‐19 and these changes normalize during the recovery phase. Alterations in ACE2 species following SARS‐CoV‐2 infection warrant further investigation regarding their potential usefulness as biomarkers for the disease process and to asses efficacy during vaccination.
Identifying high-yield genotypes under low water availability is essential for soybean climate-smart breeding. However, a major bottleneck lies in phenotyping, particularly in selecting ...cost-efficient markers associated with stress tolerance and yield stabilization. Here, we conducted in-depth phenotyping experiments in two soybean genotypes with contrasting drought tolerance, MUNASQA (tolerant) and TJ2049 (susceptible), to better understand soybean stress physiology and identify/statistically validate drought-tolerance and yield-stabilization traits as potential breeding markers. Firstly, at the critical reproductive stage (R5), the molecular differences between the genotype's responses to mild water deficit were explored through massive analysis of cDNA ends (MACE)-transcriptomic and gene ontology. MUNASQA transcriptional profile, compared to TJ2049, revealed significant differences when responding to drought. Next, both genotypes were phenotyped under mild water deficit, imposed in vegetative (V3) and R5 stages, by evaluating 22 stress-response, growth, and water-use markers, which were subsequently correlated between phenological stages and with yield. Several markers showed high consistency, independent of the phenological stage, demonstrating the effectiveness of the phenotyping methodology and its possible use for early selection. Finally, these markers were classified and selected according to their cost-feasibility, statistical weight, and correlation with yield. Here, pubescence, stomatal density, and canopy temperature depression emerged as promising breeding markers for the early selection of drought-tolerant soybeans.
Poxvirus vector Modified Vaccinia Virus Ankara (MVA) expressing HIV-1 Env, Gag, Pol and Nef antigens from clade B (termed MVA-B) is a promising HIV/AIDS vaccine candidate, as confirmed from results ...obtained in a prophylactic phase I clinical trial in humans. To improve the immunogenicity elicited by MVA-B, we have generated and characterized the innate immune sensing and the in vivo immunogenicity profile of a vector with a double deletion in two vaccinia virus (VACV) genes (C6L and K7R) coding for inhibitors of interferon (IFN) signaling pathways. The innate immune signals elicited by MVA-B deletion mutants (MVA-B ΔC6L and MVA-B ΔC6L/K7R) in human macrophages and monocyte-derived dendritic cells (moDCs) showed an up-regulation of the expression of IFN-β, IFN-α/β-inducible genes, TNF-α, and other cytokines and chemokines. A DNA prime/MVA boost immunization protocol in mice revealed that these MVA-B deletion mutants were able to improve the magnitude and quality of HIV-1-specific CD4(+) and CD8(+) T cell adaptive and memory immune responses, which were mostly mediated by CD8(+) T cells of an effector phenotype, with MVA-B ΔC6L/K7R being the most immunogenic virus recombinant. CD4(+) T cell responses were mainly directed against Env, while GPN-specific CD8(+) T cell responses were induced preferentially by the MVA-B deletion mutants. Furthermore, antibody levels to Env in the memory phase were slightly enhanced by the MVA-B deletion mutants compared to the parental MVA-B. These findings revealed that double deletion of VACV genes that act blocking intracellularly the IFN signaling pathway confers an immunological benefit, inducing innate immune responses and increases in the magnitude, quality and durability of the HIV-1-specific T cell immune responses. Our observations highlighted the immunomodulatory role of the VACV genes C6L and K7R, and that targeting common pathways, like IRF3/IFN-β signaling, could be a general strategy to improve the immunogenicity of poxvirus-based vaccine candidates.
The evolution of poxvirus vaccines Sánchez-Sampedro, Lucas; Perdiguero, Beatriz; Mejías-Pérez, Ernesto ...
Viruses,
04/2015, Letnik:
7, Številka:
4
Journal Article, Book Review
Recenzirano
Odprti dostop
After Edward Jenner established human vaccination over 200 years ago, attenuated poxviruses became key players to contain the deadliest virus of its own family: Variola virus (VARV), the causative ...agent of smallpox. Cowpox virus (CPXV) and horsepox virus (HSPV) were extensively used to this end, passaged in cattle and humans until the appearance of vaccinia virus (VACV), which was used in the final campaigns aimed to eradicate the disease, an endeavor that was accomplished by the World Health Organization (WHO) in 1980. Ever since, naturally evolved strains used for vaccination were introduced into research laboratories where VACV and other poxviruses with improved safety profiles were generated. Recombinant DNA technology along with the DNA genome features of this virus family allowed the generation of vaccines against heterologous diseases, and the specific insertion and deletion of poxvirus genes generated an even broader spectrum of modified viruses with new properties that increase their immunogenicity and safety profile as vaccine vectors. In this review, we highlight the evolution of poxvirus vaccines, from first generation to the current status, pointing out how different vaccines have emerged and approaches that are being followed up in the development of more rational vaccines against a wide range of diseases.
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