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Proteasomes are barrel-like cellular protein complexes responsible for the degradation of most intracellular proteins. Earlier, it has been shown that during assembly, hundreds of different cellular proteins are incorporated into retro-and herpes viruses. Among detected cellular proteins, there were different proteasome subunits (PS). Previous reports postulated the incorporation of 20S proteasome subunits and subunits of proteasome regulator complexes inside retroviruses. Here, we demonstrated the association of functional 20S proteasome with gammaretroviruses, betaretroviruses, and lentiviruses. Cleaved proteasome subunits β1, β2 and β5 were detected in tested viruses. Using fluorescent peptides and a cell-permeable proteasome activity probe, proteasome activity was detected in endogenous and exogenous retroviruses, including recombinant HIV-1. Taken together, our data favors the insertion of functional proteasomes into the retroviruses during assembly. The possible role of proteasomes in retroviruses is discussed. [ABSTRACT FROM AUTHOR]

Retroviruses perpetuate their survival by incorporating a copy of their genome into the host cell, a critical step catalyzed by the virally encoded integrase. The viral capsid plays an important role during the viral life cycle, including nuclear importation in the case of lentiviruses and integration targeting events; hence, targeting the integrase and the viral capsid is a favorable therapeutic strategy. While integrase strand transfer inhibitors (INSTIs) are recommended as first-line regimens given their high efficacy and tolerability, lenacapavir is the first capsid inhibitor and the newest addition to the HIV treatment arsenal. These inhibitors are however designed for treatment of HIV-1 infection, and their efficacy against HIV-2 remains widely understudied and inconclusive, supported only by a few limited phenotypic susceptibility studies. We therefore carried out inhibition profiling of a panel of second-generation INSTIs and lenacapavir against HIV-2 in cell culture, utilizing pseudovirion inhibition profiling assays. Our results show that the tested INSTIs and lenacapavir exerted excellent efficacy against ROD-based HIV-2 integrase. We further evaluated the efficacy of raltegravir and other INSTIs against different variants of SARS-CoV-2; however, contrary to previous in silico findings, the inhibitors did not demonstrate significant antiviral activity. [ABSTRACT FROM AUTHOR]

The evolutionary pressures exerted by viral infections have led to the development of various cellular proteins with potent antiviral activities, some of which are known as antiviral restriction factors. TRIpartite Motif-containing protein 5 alpha (TRIM5α) is a well-studied restriction factor of retroviruses that exhibits virus- and host-species-specific functions in protecting against cross-primate transmission of specific lentiviruses. This specificity is achieved at the level of the host gene through positive selection predominantly within its C-terminal B30.2/PRYSPRY domain, which is responsible for the highly specific recognition of retroviral capsids. However, more recent work has challenged this paradigm, demonstrating TRIM5α as a restriction factor for retroelements as well as phylogenetically distinct viral families, acting similarly through the recognition of viral gene products via B30.2/PRYSPRY. This spectrum of antiviral activity raises questions regarding the genetic and structural plasticity of this protein as a mediator of the recognition of a potentially diverse array of viral molecular patterns. This review highlights the dynamic evolutionary footprint of the B30.2/PRYSPRY domain in response to retroviruses while exploring the guided 'specificity' conferred by the totality of TRIM5α's additional domains that may account for its recently identified promiscuity. [ABSTRACT FROM AUTHOR]

The field of retroviral integration research has a long history that started with the provirus hypothesis and subsequent discoveries of the retroviral reverse transcriptase and integrase enzymes. Because both enzymes are essential for retroviral replication, they became valued targets in the effort to discover effective compounds to inhibit HIV-1 replication. In 2007, the first integrase strand transfer inhibitor was licensed for clinical use, and subsequently approved second-generation integrase inhibitors are now commonly co-formulated with reverse transcriptase inhibitors to treat people living with HIV. International meetings specifically focused on integrase and retroviral integration research first convened in 1995, and this paper is part of the Viruses Special Issue on the 7th International Conference on Retroviral Integration, which was held in Boulder Colorado in the summer of 2023. Herein, we overview key historical developments in the field, especially as they pertain to the development of the strand transfer inhibitor drug class. Starting from the mid-1990s, research advancements are presented through the lens of the international conferences. Our overview highlights the impact that regularly scheduled, subject-specific international meetings can have on community-building and, as a result, on field-specific collaborations and scientific advancements. [ABSTRACT FROM AUTHOR]

The epitranscriptomic modification m6A is a prevalent RNA modification that plays a crucial role in the regulation of various aspects of RNA metabolism. It has been found to be involved in a wide range of physiological processes and disease states. Of particular interest is the role of m6A machinery and modifications in viral infections, serving as an evolutionary marker for distinguishing between self and non-self entities. In this review article, we present a comprehensive overview of the epitranscriptomic modification m6A and its implications for the interplay between viruses and their host, focusing on immune responses and viral replication. We outline future research directions that highlight the role of m6A in viral nucleic acid recognition, initiation of antiviral immune responses, and modulation of antiviral signaling pathways. Additionally, we discuss the potential of m6A as a prognostic biomarker and a target for therapeutic interventions in viral infections. [ABSTRACT FROM AUTHOR]

DNA oncoviruses represent an intriguing subject due to their involvement in oncogenesis. These viruses have evolved mechanisms to manipulate the host immune response, facilitating their persistence and actively contributing to carcinogenic processes. This paper describes the complex interactions between DNA oncoviruses and the innate immune system, with a particular emphasis on the cGAS-STING pathway. Exploring these interactions highlights that DNA oncoviruses strategically target and subvert this pathway, exploiting its vulnerabilities for their own survival and proliferation within the host. Understanding these interactions lays the foundation for identifying potential therapeutic interventions. Herein, we sought to contribute to the ongoing efforts in advancing our understanding of the innate immune system in oncoviral pathogenesis. [ABSTRACT FROM AUTHOR]

PYHIN proteins are only found in mammals and play key roles in the defense against bacterial and viral pathogens. The corresponding gene locus shows variable deletion and expansion ranging from 0 genes in bats, over 1 in cows, and 4 in humans to a maximum of 13 in mice. While initially thought to act as cytosolic immune sensors that recognize foreign DNA, increasing evidence suggests that PYHIN proteins also inhibit viral pathogens by more direct mechanisms. Here, we examined the ability of all 13 murine PYHIN proteins to inhibit HIV-1 and murine leukemia virus (MLV). We show that overexpression of p203, p204, p205, p208, p209, p210, p211, and p212 strongly inhibits production of infectious HIV-1; p202, p207, and p213 had no significant effects, while p206 and p214 showed intermediate phenotypes. The inhibitory effects on infectious HIV-1 production correlated significantly with the suppression of reporter gene expression by a proviral Moloney MLV-eGFP construct and HIV-1 and Friend MLV LTR luciferase reporter constructs. Altogether, our data show that the antiretroviral activity of PYHIN proteins is conserved between men and mice and further support the key role of nuclear PYHIN proteins in innate antiviral immunity. [ABSTRACT FROM AUTHOR]

Approximately 15–20% of global cancer cases are attributed to virus infections. Oncoviruses employ various molecular strategies to enhance replication and persistence. Human cytomegalovirus (HCMV), acting as an initiator or promoter, enables immune evasion, supporting tumor growth. HCMV activates pro-oncogenic pathways within infected cells and direct cellular transformation. Thus, HCMV demonstrates characteristics reminiscent of oncoviruses. Cumulative evidence emphasizes the crucial roles of EZH2 and Myc in oncogenesis and stemness. EZH2 and Myc, pivotal regulators of cellular processes, gain significance in the context of oncoviruses and HCMV infections. This axis becomes a central focus for comprehending the mechanisms driving virus-induced oncogenesis. Elevated EZH2 expression is evident in various cancers, making it a prospective target for cancer therapy. On the other hand, Myc, deregulated in over 50% of human cancers, serves as a potent transcription factor governing cellular processes and contributing to tumorigenesis; Myc activates EZH2 expression and induces global gene expression. The Myc/EZH2 axis plays a critical role in promoting tumor growth in oncoviruses. Considering that HCMV has been shown to manipulate the Myc/EZH2 axis, there is emerging evidence suggesting that HCMV could be regarded as a potential oncovirus due to its ability to exploit this critical pathway implicated in tumorigenesis. [ABSTRACT FROM AUTHOR]

Understanding the local epidemiology of feline leukaemia virus (FeLV) and feline immunodeficiency virus (FIV) in Hong Kong will inform retrovirus prevention strategies. Domestic cat hepadnavirus (DCH), a novel hepatitis-B-like virus, is commonly detected among client-owned cats in Hong Kong, but community cats have not been studied. The aims of this study were to investigate the frequency and potential risk factors for (i) FeLV and FIV among community and client-owned cats and (ii) perform molecular detection of DCH among community cats in Hong Kong. Blood samples from 713 cats were obtained from client-owned (n = 415, residual diagnostic) and community cats (n = 298, at trap-neuter-return). Point-of-care (POC) testing for FeLV antigen and feline immunodeficiency virus (FIV) anti-p15 and p24 antibodies was performed. FeLV-positive samples were progressed to p27 sandwich enzyme-linked immunosorbent assay. Whole blood DNA was tested with qPCRs for FeLV U3 and gag, and nested PCRs where additional information was required. DCH qPCR was performed on a subset of community cats (n = 193). A single, regressive, FeLV infection was detected in a client-owned cat (1/415 FeLV U3 qPCR positive, 0.2%, 95% CI 0.0–1.3%). Five/415 client-owned cats tested presumably false FeLV-antigen positive (qPCR negative). No markers of FeLV infection were detected in community cats (0/298; 0%). FIV seroprevalence was much higher in community cats (46/298, 15.4%) than in client-owned cats (13/415, 3.1%) (p < 0.001). Mixed breed was a risk factor for FIV infection in client-owned cats. Neither sex nor age were associated with FIV infection. DCH DNA was detected in 34/193 (17.6%) community cats (median viral load 6.32 × 103 copies/reaction). FeLV infection is rare in Hong Kong, negatively impacting the positive predictive value of diagnostic tests. FeLV-antigen testing remains the screening test of choice, but confirmation of a positive result using FeLV qPCR is essential. FIV infection is common in community cats and the absence of a sex predisposition, seen previously in cats managed similarly, raises questions about virus-transmission dynamics in these groups. DCH infection is very common in Hong Kong, both in client-owned and community cats, highlighting the importance of understanding the pathogenic potential of this virus for cats. [ABSTRACT FROM AUTHOR]

Interindividual variability in drug response is a major problem in the prescription of pharmacological treatments. The therapeutic effect of drugs can be influenced by human genes. Pharmacogenomic guidelines for individualization of treatment have been validated and used for conventional dosage forms. However, drugs can often target non-specific areas and produce both desired and undesired pharmacological effects. The use of nanoparticles, liposomes, or other available forms for drug formulation could help to overcome the latter problem. Virus-like particles based on retroviruses could be a potential envelope for safe and efficient drug formulations. Human endogenous retroviruses would make it possible to overcome the host immune response and deliver drugs to the desired target. PEG10 is a promising candidate that can bind to mRNA because it is secreted like an enveloped virus-like extracellular vesicle. PEG10 is a retrotransposon-derived gene that has been domesticated. Therefore, formulations with PEG10 may have a lower immunogenicity. The use of existing knowledge can lead to the development of suitable drug formulations for the precise treatment of individual diseases. [ABSTRACT FROM AUTHOR]

Cat ownership is common in Chile, but data on the regional prevalence of infectious agents are limited. A sero-molecular survey of 120 client- or shelter-owned domestic cats in greater Santiago was performed. Whole blood DNA was tested for the novel hepatitis-B-like virus, domestic cat hepadnavirus (DCH) by conventional PCR (cPCR) and quantitative PCR (qPCR), and for feline leukaemia virus (FeLV) by qPCR. Point-of-care serology for FeLV p27 antigen and antibodies recognising feline immunodeficiency virus (FIV) p15 and p24 was performed. DCH DNA was detected in the serum of 2/120 cats (1.67%). Sequencing and phylogenetic analysis showed that the DCH detected in Chile occupies a position outside the main clustering of DCH in the near-complete genome tree. Progressive (antigen-positive, provirus-positive) and regressive (antigen-negative, provirus-positive) FeLV infections were identified in 6/120 (5%) and 9/120 (7.5%) of cats. A total of 2/120 (1.7%) cats had dual FeLV/FIV infection, and another 2 cats had FIV infection alone. This study shows that the global footprint of DCH includes South America with a low molecular frequency in Chile, similar to that reported in the USA. Progressive FeLV infection is relatively common in urban Chile, and male cats are at greater risk than females. Testing and control measures for pathogenic retroviruses are indicated. The potential impact of FeLV, FIV and DCH on Chile's wildcat species is worthy of further investigation. [ABSTRACT FROM AUTHOR]

Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections in the host genome. Although mutations and silencing mechanisms impair their original role in viral replication, HERVs are believed to play roles in various biological processes. Long interspersed nuclear elements (LINEs) are non-LTR retrotransposons that have a lifecycle resembling that of retroviruses. Although LINE expression is typically silenced in somatic cells, it also contributes to various biological processes. The aberrant expression of HERVs and LINEs is closely associated with the development of cancer and/or immunological diseases, suggesting that they are integrated into various pathways related to the diseases. HERVs/LINEs control gene expression depending on the context as promoter/enhancer elements. Some RNAs and proteins derived from HERVs/LINEs have oncogenic potential, whereas others stimulate innate immunity. Non-retroviral endogenous viral elements (nrEVEs) are a novel type of virus-like element in the genome. nrEVEs may also be involved in host immunity. This article provides a current understanding of how these elements impact cellular physiology in cancer development and innate immunity, and provides perspectives for future studies. [ABSTRACT FROM AUTHOR]

Simple Summary: Small ruminant lentiviruses (SRLVs) are a group of highly diverse viruses responsible for global infections in goats and sheep. The purpose of this study was to genetically characterize SRLVs circulating in Romania. A total of 122 samples from pulmonary and lung lymph nodes of slaughtered sheep were examined. The obtained gag-pol and gag sequences from Romanian SRLV strains were compared with available GenBank strains, and the results showed that the Romanian sequences were associated with strains A2 and A3 based on gag-pol sequences and with subtypes A3 and A17 based on gag sequences. In addition, the Romanian sequences showed some specific mutations in epitope 3, which may reflect their evolution. This study describes for the first time SRLV sequences detected in Romanian sheep, providing basic information on the subtypes circulating in Romania. Small ruminant lentiviruses (SRLVs) are a group of retroviruses that cause multisystem chronic diseases in goats and sheep and lead to production losses in these animals, negatively affecting animal health and welfare. Although molecular characterization of SRLV field isolates has been performed in many countries, there is currently no information on SRLV genotypes circulating in sheep and goats in Romania. Therefore, the main objective of this study was to conduct a molecular and phylogenetic analysis of SRLVs from Romania and determine the degree of genetic relatedness of the obtained sequences to other known SRLV reference strains. A total of 81 sheep lung tissue samples and 41 sheep lung lymph node samples were tested using nested real-time PCR, and samples positive for real-time PCR were used to amplify an 800 bp gag-pol fragment and an overlapping 625 bp fragment of the gag gene. Pairwise DNA distance and phylogenetic analysis showed that the Romanian SRLV strains were closely related to the A2 and A3 strains based on gag-pol sequences and to the A3 and A17 subtypes based on gag sequences. No recombination events were found. Our results revealed that the Romanian sequences have similar epitope patterns to other existing subtypes, although E/K and R/K mutations in epitope 3 were found only in the Romanian sequences, which may have potential value in serological diagnosis. This study is the first report on the genetic characterization of SRLV strains circulating in Romania and provides new information on SRLV heterogeneity. Further detailed studies should be conducted to better understand the divergence of SRLV Romanian strains. [ABSTRACT FROM AUTHOR]

Simple Summary: Acute Myeloid Leukemia is the most common leukemia in adults and has a dismal prognosis. An allogeneic bone marrow transplant provides the best curative approach. However, due to its related morbidity and mortality, the decision is based on risk assessment at diagnosis and response to therapy. Accurate assessment of molecular Minimal Residual Disease (MRD) has provided a powerful tool to assess the depth of response and risk of relapse. However, validated and standardized molecular MRD is currently limited to typical NPM1 mutations and core-binding factor translocations. To allow for a better standardization of other identified mutations, we constructed a vector that bears both the sequence for the mutation of interest and the ABL1 gene, thus allowing us to calculate the mutation copy number using the inherent ABL1 gene standards. We have implanted this approach in several identified mutations including atypical NPM1, IDH1/2 and RUNX1. Quantitative PCR for specific mutation is being increasingly used in Acute Myeloid Leukemia (AML) to assess Measurable Residual Disease (MRD), allowing for more tailored clinical decisions. To date, standardized molecular MRD is limited to typical NPM1 mutations and core binding factor translocations, with clear prognostic and clinical implications. The monitoring of other identified mutations lacks standardization, limiting its use and incorporation in clinical trials. To overcome this problem, we designed a plasmid bearing both the sequence of the mutation of interest and the ABL reference gene. This allows the use of commercial standards for ABL to determine the MRD response in copy number. We provide technical aspects of this approach as well as our experience with 19 patients with atypical NPM1, RUNX1 and IDH1/2 mutations. In all cases, we demonstrate a correlation between response and copy number. We further demonstrate how copy number monitoring can modulate the clinical management. Taken together, we provide proof of concept of a novel yet simple tool, which allows in-house MRD monitoring for identified mutations, with ABL-based commercial standards. This approach would facilitate large multi-center studies assessing the clinical relevance of selected MRD monitoring. [ABSTRACT FROM AUTHOR]

SERINC5 is a restriction factor that becomes incorporated into nascent retroviral particles, impairing their ability to infect target cells. In turn, retroviruses have evolved countermeasures against SERINC5. For instance, the primate lentiviruses (HIV and SIV) use Nef, Moloney Murine Leukemia Virus (MLV) uses GlycoGag, and Equine Infectious Anemia Virus (EIAV) uses S2 to remove SERINC5 from the plasma membrane, preventing its incorporation into progeny virions. Recent studies have shown that SERINC5 also restricts other viruses, such as Hepatitis B Virus (HBV) and Classical Swine Fever Virus (CSFV), although through a different mechanism, suggesting that SERINC5 can interfere with multiple stages of the virus life cycle. To investigate whether SERINC5 can also impact other steps of the replication cycle of HIV, the effects of SERINC5 on viral transcripts, proteins, and virus progeny size were studied. Here, we report that SERINC5 causes significant defects in HIV gene expression, which impacts virion production. While the underlying mechanism is still unknown, we found that the restriction occurs at the transcriptional level and similarly affects plasmid and non-integrated proviral DNA (ectopic or non-self-DNA). However, SERINC5 causes no defects in the expression of viral RNA, host genes, or proviral DNA that is integrated in the cellular genome. Hence, our findings reveal that SERINC5's actions in host defense extend beyond blocking virus entry. [ABSTRACT FROM AUTHOR]

The endosomal sorting complex required for transport (ESCRT) machinery is essential for the budding of retroviruses such as human immunodeficiency virus (HIV) and bovine foamy virus (BFV), which rely on their late domain to recruit ESCRT complexes to facilitate budding. However, the impact of intracellular host proteins on BFV budding remains poorly understood. In this study, we aimed to investigate the impact of CCL2 on BFV budding and interactions with key host proteins. Our results indicate that CCL2 promotes BFV budding in an ALG-2-interacting protein X (Alix)-dependent manner by enhancing the interaction between Alix and BFV Gag (BGag). Notably, we found a link between Alix, BGag and CCL2, with Alix mediating the interaction between the latter two. Furthermore, we observed that natural host bovine CCL2 also has a facilitating role in the budding process of BFV, similar to human CCL2. Taken together, these results demonstrate that CCL2 promotes BFV budding by enhancing the Alix-BGag association. [ABSTRACT FROM AUTHOR]

Endogenous retroviruses (ERVs) are integrated into host DNA as the result of ancient germ line infections, primarily by extinct exogenous retroviruses. Thus, vertebrates' genomes contain thousands of ERV copies, providing a "fossil" record for ancestral retroviral diversity and its evolution within the host genome. Like other retroviruses, the ERV proviral sequence consists of gag, pro, pol, and env genes flanked by long terminal repeats (LTRs). Particularly, the env gene encodes for the envelope proteins that initiate the infection process by binding to the host cellular receptor(s), causing membrane fusion. For this reason, a major element in understanding ERVs' evolutionary trajectory is the characterization of env changes over time. Most of the studies dedicated to ERVs' env have been aimed at finding an "actual" physiological or pathological function, while few of them have focused on how these genes were once acquired and modified within the host. Once acquired into the organism, genome ERVs undergo common cellular events, including recombination. Indeed, genome recombination plays a role in ERV evolutionary dynamics. Retroviral recombination events that might have been involved in env divergence include the acquisition of env genes from distantly related retroviruses, env swapping facilitating multiple cross-species transmission over millions of years, ectopic recombination between the homologous sequences present in different positions in the chromosomes, and template switching during transcriptional events. The occurrence of these recombinational events might have aided in shaping retroviral diversification and evolution until the present day. Hence, this review describes and discusses in detail the reported recombination events involving ERV env to provide the basis for further studies in the field. [ABSTRACT FROM AUTHOR]

Feline immunodeficiency virus (FIV) is a lentivirus in the family Retroviridae that infects domestic cats resulting in an immunodeficiency disease featuring a progressive and profound decline in multiple sets of peripheral lymphocytes. Despite compelling evidence of FIV-associated immunopathology, there are conflicting data concerning the clinical effects of FIV infection on host morbidity and mortality. To explore FIV-associated immunopathogenesis and clinical disease, we experimentally inoculated a cohort of four specific pathogen-free kittens with a biological isolate of FIV clade C and continuously monitored these animals along with two uninfected control animals for more than thirteen years from the time of inoculation to the humane euthanasia endpoint. Here, we report the results obtained during the late asymptomatic and terminal phases of FIV infection in this group of experimentally FIV-infected cats. [ABSTRACT FROM AUTHOR]

The suitability of an animal model for use in studying human diseases relies heavily on the similarities between the two species at the genetic, epigenetic, and metabolic levels. However, there is a lack of consistent data from different animal models at each level to evaluate this suitability. With the availability of genome sequences for many mammalian species, it is now possible to compare animal models based on genomic similarities. Herein, we compare the coding sequences (CDSs) of five mammalian models, including rhesus macaque, marmoset, pig, mouse, and rat models, with human coding sequences. We identified 10,316 conserved CDSs across the five organisms and the human genome based on sequence similarity. Mapping the human-disease-associated single-nucleotide polymorphisms (SNPs) from these conserved CDSs in each species has identified species-specific associations with various human diseases. While associations with a disease such as colon cancer were prevalent in multiple model species, the rhesus macaque showed the most model-specific human disease associations. Based on the percentage of disease-associated SNP-containing genes, marmoset models are well suited to study many human ailments, including behavioral and cardiovascular diseases. This study demonstrates a genomic similarity evaluation of five animal models against human CDSs that could help investigators select a suitable animal model for studying their target disease. [ABSTRACT FROM AUTHOR]

Adult camel leukosis is an emerging hematological and neoplastic disease in dromedaries. It has been hypothesized that bovine leukemia virus (BLV) or its genetic variants may be associated with adult camel leukosis. In this study, we used next-generation sequencing (NGS) to detect all possible viruses in five lung samples from five dromedaries with histopathological evidence of adult camel leukosis and four tissue samples from two control dromedaries. A total throughput of 114.7 Gb was achieved, with an average of 12.7 Gb/sample. For each sample, all the pair-end 151-bp reads were filtered to remove rRNA sequences, bacterial genomes and redundant sequences, resulting in 1–7 Gb clean reads, of which <3% matched to viruses. The largest portion of these viral sequences was composed of bacterial phages. About 100–300 reads in each sample matched "multiple sclerosis-associated retrovirus", but manual analysis showed that they were only repetitive sequences commonly present in mammalian genomes. All viral reads were also extracted for analysis, confirming that no BLV or its genetic variants or any other virus was detected in the nine tissue samples. NGS is not only useful for detecting microorganisms associated with infectious diseases, but also important for excluding an infective cause in scenarios where such a possibility is suspected. [ABSTRACT FROM AUTHOR]

Simple Summary: Human endogenous retrovirus (HERV) plays important roles in the development of cancer, and most studies use data from The Cancer Genome Atlas to analyze the whole HERV alterations in cancer cells. For HCCs, most studies have focused on LINE-1 and specific HERVs to explore their importance. In this study, we used our total RNA sequencing data from 254 Taiwanese HCCs and many bioinformatic tools to analyze HERV alterations, and then explored the correlations between HERV activation and pathways and certain gene panels. Unique pathways for a higher expression of survival-related HERVs including immunity and infection, lipid and atherosclerosis, MAPK and NF-kB signaling, and cytokine-cytokine receptor interaction pathways were activated; the mRNA surveillance pathway, nucleocytoplasmic transport, ribosome biogenesis, and transcriptional misregulation in cancer pathways were suppressed. We found that many overexpressed HERV-related nearby genes were correlated with high HERV activation and poor survival. The implementation of comprehensive and integrated approaches to assess HERV expression and their association with specific pathways is poised to offer novel companion diagnostics and therapeutic strategies for HCC. Background: Human endogenous retroviruses (HERVs) play an important role in the development of cancer and many diseases. Here, we comprehensively explored the impact of HERVs on hepatocellular carcinomas (HCCs). Methods: We employed Telescope to identify HERVs and quantify their expression in the total RNA sequencing data obtained from 254 HCC samples, comprising 254 tumor tissues and 34 matched normal tissues. Results: In total, 3357 locus-specific activations of HERVs were differentially expressed, and 180 were correlated with patient survival. Using these 180 HERVs for classification, we found four subgroups with survival correlation. Higher expression levels of the 180 HERVs were correlated with poorer survival, while age, AFP, some mutations, and copy and structural variants differed among subgroups. The differential expression of host genes in high expression of these 180 HERVs primarily involved the activation of pathways related to immunity and infection, lipid and atherosclerosis, MAPK and NF-kB signaling, and cytokine–cytokine receptor interactions. Conversely, there was a suppression of pathways associated with RNA processing, including nucleocytoplasmic transport, surveillance and ribosome biogenesis, and transcriptional misregulation in cancer pathways. Almost all genes involved in HERV activation restriction, KRAB zinc finger proteins, RNA nucleocytoplasmic transport, stemness, HLA and antigen processing and presentation, and immune checkpoints were overexpressed in cancerous tissues, and many over-expressed HERV-related nearby genes were correlated with high HERV activation and poor survival. Twenty-three immune and stromal cells showed higher expression in non-cancerous than cancerous tissues, and seven were correlated with HERV activation. Small-molecule modulation of alternative splicing (AS) altered the expression of survival-related HERVs and their activation-related genes, as well as nearby genes. Conclusion: Comprehensive and integrated approaches for evaluating HERV expression and their correlation with specific pathways have the potential to provide new companion diagnostics and therapeutic strategies for HCC. [ABSTRACT FROM AUTHOR]

The CRISPR/Cas system has a broad range of possible medical applications, but its clinical translation has been hampered, particularly by the lack of safe and efficient vector systems mediating the short-term expression of its components. Recently, different virus-like particles (VLPs) have been introduced as promising vectors for the delivery of CRISPR/Cas genome editing components. Here, we characterized and directly compared three different types of retrovirus-based (R) VLPs, two derived from the γ-retrovirus murine leukemia virus (gRVLPs and "enhanced" egRVLPs) and one from the lentivirus human immunodeficiency virus, HIV (LVLPs). First, we unified and optimized the production of the different RVLPs. To ensure maximal comparability of the produced RVLPs, we adapted several assays, including nanoparticle tracking analysis (NTA), multi-parametric imaging flow cytometry (IFC), and Cas9-ELISA, to analyze their morphology, surface composition, size, and concentration. Next, we comparatively tested the three RVLPs targeting different genes in 293T model cells. Using identical gRNAs, we found egRVLPs to mediate the most efficient editing. Functional analyses indicated better cargo (i.e., Cas9) transfer and/or release as the underlying reason for their superior performance. Finally, we compared on- and off-target activities of the three RVLPs in human-induced pluripotent stem cells (hiPSC) exploiting the clinically relevant C-C motif chemokine receptor 5 (CCR5) as the target. Again, egRVLPs facilitated the highest, almost 100% knockout rates, importantly with minimal off-target activity. In conclusion, in direct comparison, egRVLPs were the most efficient RVLPs. Moreover, we established methods for in-depth characterization of VLPs, facilitating their validation and thus more predictable and safe application. [ABSTRACT FROM AUTHOR]

Urinary tract infections (UTIs) are one of the most frequent bacterial infections in the world, both in the hospital and community settings. Uropathogenic Escherichia coli (UPEC) are the predominant etiological agents causing UTIs. Extended-spectrum beta-lactamase (ESBL) production is a prominent mechanism of resistance that hinders the antimicrobial treatment of UTIs caused by UPEC and poses a substantial danger to the arsenal of antibiotics now in use. As bacteria have several methods to counteract the effects of antibiotics, identifying new potential drug targets may help in the design of new antimicrobial agents, and in the control of the rising trend of antimicrobial resistance (AMR). The public availability of the entire genome sequences of humans and many disease-causing organisms has accelerated the hunt for viable therapeutic targets. Using a unique, hierarchical, in silico technique using computational tools, we discovered and described potential therapeutic drug targets against the ESBL-producing UPEC strain NA114. Three different sets of proteins (chokepoint, virulence, and resistance genes) were explored in phase 1. In phase 2, proteins shortlisted from phase 1 were analyzed for their essentiality, non-homology to the human genome, and gut flora. In phase 3, the further shortlisted putative drug targets were qualitatively characterized, including their subcellular location, broad-spectrum potential, and druggability evaluations. We found seven distinct targets for the pathogen that showed no similarity to the human proteome. Thus, possibilities for cross-reactivity between a target-specific antibacterial and human proteins were minimized. The subcellular locations of two targets, ECNA114_0085 and ECNA114_1060, were predicted as cytoplasmic and periplasmic, respectively. These proteins play an important role in bacterial peptidoglycan biosynthesis and inositol phosphate metabolism, and can be used in the design of drugs against these bacteria. Inhibition of these proteins will be helpful to combat infections caused by MDR UPEC. [ABSTRACT FROM AUTHOR]

The transmission of viruses from one host to another typically occurs through horizontal or vertical pathways. The horizontal pathways include transmission amongst individuals, usually through bodily fluids or excretions, while vertical transmission transpires from mother to their offspring, either during pregnancy, childbirth, or breastfeeding. While there are more than 200 human pathogenic viruses to date, only a small number of them are known to be transmitted via breast milk, including cytomegalovirus (CMV), human immunodeficiency virus type 1 (HIV-1), and human T cell lymphotropic virus type 1 (HTLV-1), the latter two belonging to the family Retroviridae. Breast milk transmission is a common characteristic among mammalian retroviruses, but there is a lack of reports summarizing our knowledge regarding this route of transmission of mammalian retroviruses. Here, we provide an overview of the transmission of mammalian exogenous retroviruses with a focus on Orthoretrovirinae, and we highlight whether they have been described or suspected to be transmitted through breast milk, covering various species. We also elaborate on the production and composition of breast milk and discuss potential entry sites of exogenous mammalian retroviruses during oral transmission. [ABSTRACT FROM AUTHOR]

Simple Summary: Endogenous retroviruses (ERVs) are integrated retroviral elements that cover 8% of the human genome, representing thereby four-fold the fraction of the genome encoding for protein-coding genes. Overall, their expression represents up to 0.5% of all non-rRNA transcripts in mesothelioma, and some are specifically re-activated. This part of the genome has been considered until recently "junk DNA" or "DNA dark matter". However, analysis of ERV expression has recently gained attention in several cancers, especially in the context of immunotherapy. In this review, our aim is to raise the curiosity of non-specialists by illustrating the potential of exploring the expression of "DNA dark matter" for prognosis and immunotherapy, potentially as predictive biomarkers in mesothelioma. Recent high-throughput RNA sequencing technologies have confirmed that a large part of the non-coding genome is transcribed. The priority for further investigations is nevertheless generally given in cancer to coding sequences, due to the obvious interest of finding therapeutic targets. In addition, several RNA-sequencing pipelines eliminate repetitive sequences, which are difficult to analyze. In this review, we shall focus on endogenous retroviruses. These sequences are remnants of ancestral germline infections by exogenous retroviruses. These sequences represent 8% of human genome, meaning four-fold the fraction of the genome encoding for proteins. These sequences are generally mostly repressed in normal adult tissues, but pathological conditions lead to their de-repression. Specific mesothelioma-associated endogenous retrovirus expression and their association to clinical outcome is discussed. [ABSTRACT FROM AUTHOR]

The double infection between CRFs established more optimal conditions for the second-generation recombination, and many second-generation recombinants were represented by the recombination of CRF01 AE and CRF07 BC fragments, such as CRF79 0107 [[11]], CRF80 0107 [[12]], CRF102 01075 [[13]], CRF109 0107 [[14]], CR125 0107 [[15]], and others [[16], [18], [20], [22], [24]]. However, when two different RNA viruses infect the same cell, they can undergo two forms of recombination, both leading to antigenic shifts: RNA recombination and reassortment, with the latter restricted to viruses with segmented genomes [[1]]. RNA viruses have developed notable strategies to evolve and escape host immunity. Although recombination is often represented as a form of sexual reproduction, there is little evidence that recombination in RNA viruses evolved as a way of creating advantageous genotypes or removing deleterious mutations. [Extracted from the article]

Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease characterized by the progressive elevation of pulmonary arterial pressures. It is becoming increasingly apparent that inflammation contributes to the pathogenesis and progression of PAH. Several viruses are known to cause PAH, such as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), human endogenous retrovirus K(HERV-K), and human immunodeficiency virus (HIV), in part due to acute and chronic inflammation. In this review, we discuss the connections between HERV-K, HIV, SARS-CoV-2, and PAH, to stimulate research regarding new therapeutic options and provide new targets for the treatment of the disease. [ABSTRACT FROM AUTHOR]

Retroviruses, especially the pathogenic human immunodeficiency virus type 1 (HIV-1), have severely threatened human health for decades. Retroviruses can form stable latent reservoirs via retroviral DNA integration into the host genome, and then be temporarily transcriptional silencing in infected cells, which makes retroviral infection incurable. Although many cellular restriction factors interfere with various steps of the life cycle of retroviruses and the formation of viral latency, viruses can utilize viral proteins or hijack cellular factors to evade intracellular immunity. Many post-translational modifications play key roles in the cross-talking between the cellular and viral proteins, which has greatly determined the fate of retroviral infection. Here, we reviewed recent advances in the regulation of ubiquitination and SUMOylation in the infection and latency of retroviruses, focusing on both host defense- and virus counterattack-related ubiquitination and SUMOylation system. We also summarized the development of ubiquitination- and SUMOylation-targeted anti-retroviral drugs and discussed their therapeutic potential. Manipulating ubiquitination or SUMOylation pathways by targeted drugs could be a promising strategy to achieve a "sterilizing cure" or "functional cure" of retroviral infection. [ABSTRACT FROM AUTHOR]

Simple Summary: Epstein–Barr virus (EBV) is a gamma-herpesvirus associated with a broad variety of cancers. It employs two modes of viral replication, i.e., latent and lytic cycles in which both can contribute to oncogenesis. Increasing evidence supports the contribution of the lytic cycle in cancer development while only a limited number of lytic proteins have been characterized in detail. This review aims to summarize the currently known tumorigenic properties of the lytic proteins based on their contribution to the hallmarks of cancer and to postulate the roles of some partially characterized or uncharacterized lytic proteins based on their homologs in other herpesviruses and oncoviruses. Epstein–Barr virus (EBV) is a prevalent human gamma-herpesvirus that infects the majority of the adult population worldwide and is associated with several lymphoid and epithelial malignancies. EBV displays a biphasic life cycle, namely, latent and lytic replication cycles, expressing a diversity of viral proteins. Among the EBV proteins being expressed during both latent and lytic cycles, the oncogenic roles of EBV lytic proteins are largely uncharacterized. In this review, the established contributions of EBV lytic proteins in tumorigenesis are summarized according to the cancer hallmarks displayed. We further postulate the oncogenic properties of several EBV lytic proteins by comparing the evolutionary conserved oncogenic mechanisms in other herpesviruses and oncoviruses. [ABSTRACT FROM AUTHOR]

Simple Summary: Long non-coding RNA plays an essential role in the occurrence and development of prostate cancer. Drug re-sistance in tumor cells is one of the main reasons that affects the effectiveness of chemotherapy in cancer patients. The immunogenicity of the tumor is edited, and various immunosuppressive mechanisms that enable disease pro-gression are acquired, causing the tumor cells to evade the surveillance of the immune system, leading to immune evasion and drug resistance of the tumor cells. The lncRNA related to cellular immunity was obtained by bioin-formatics analysis, and the lncRNA-miRNA-mRNA regulatory network was constructed to study the mechanism of chemotherapy resistance in colon cancer cells and to obtain key genes for tumor cell resistance. Long noncoding RNAs (LncRNAs) are very important in the way that docetaxel resistance (DR) happens in prostate cancer (PCa) patients. ImmuneScore and StromalScore were calculated using PCa-related expression data from TCGA and the ESTIMATE algorithm. We finally found the DEGs that were related to the immune system and the stroma of the patients by making profiles of the DEGs in ImmuneScore and StromalScore. The CancerSubtypes algorithm identified prognosis-related PCa subtypes, and the GSVA assessed their pathway activity. A UniCox regression analysis was used to identify a prognosis-related differential gene set. We then used intersection analysis to identify immunological and prognostic (IP)-related genes (IPGs). The coexpression of long noncoding RNAs (lncRNAs) and IPGs was used to identify IP-related lncRNAs (IPLs). Three methods (SVM-RFE, random forest, and LASSO) were used to find genes that overlap in the GEO database. A gene signature was then validated by building an ROC curve. CIBERSORT technology was used to look at the possibility of a link between the gene signature and immune cells. LncRNA–miRNA pairs and miRNA–mRNA pairs from the miRDB and TargetScan databases were used to construct the ERVH48-1-miR-4784-WNT2B ceRNA regulation network. The concentration of docetaxel elevated the expression of ERVH48-1. Overexpression of ERVH48-1 increased PCa-DR cell proliferation, invasion, and migration while inhibiting apoptosis. ERVH48-1 increased the tumorigenicity of PCa-DR cells in nude mice. ERVH48-1, acting as a ceRNA, targeted miR-4784 to increase WNT2B expression. ICG001 therapy increased Wnt/-catenin signaling activity in PCa-DR cells by inhibiting ERVH48-1. Finally, ERVH48-1 increased docetaxel resistance in a WNT2B-dependent manner via the miR-4784/Wnt/-catenin pathway. [ABSTRACT FROM AUTHOR]

The recent COVID-19 crisis has highlighted the importance of RNA-based viruses. The most prominent members of this group are SARS-CoV-2 (coronavirus), HIV (human immunodeficiency virus), EBOV (Ebola virus), DENV (dengue virus), HCV (hepatitis C virus), ZIKV (Zika virus), CHIKV (chikungunya virus), and influenza A virus. With the exception of retroviruses which produce reverse transcriptase, the majority of RNA viruses encode RNA-dependent RNA polymerases which do not include molecular proofreading tools, underlying the high mutation capacity of these viruses as they multiply in the host cells. Together with their ability to manipulate the immune system of the host in different ways, their high mutation frequency poses a challenge to develop effective and durable vaccination and/or treatments. Consequently, the use of antiviral targeting agents, while an important part of the therapeutic strategy against infection, may lead to the selection of drug-resistant variants. The crucial role of the host cell replicative and processing machinery is essential for the replicative cycle of the viruses and has driven attention to the potential use of drugs directed to the host machinery as therapeutic alternatives to treat viral infections. In this review, we discuss small molecules with antiviral effects that target cellular factors in different steps of the infectious cycle of many RNA viruses. We emphasize the repurposing of FDA-approved drugs with broad-spectrum antiviral activity. Finally, we postulate that the ferruginol analog (18-(phthalimide-2-yl) ferruginol) is a potential host-targeted antiviral. [ABSTRACT FROM AUTHOR]

Retroviral integration site targeting is not random and plays a critical role in expression and long-term survival of the integrated provirus. To better understand the genomic environment surrounding retroviral integration sites, we performed a meta-analysis of previously published integration site data from evolutionarily diverse retroviruses, including new experimental data from HIV-1 subtypes A, B, C and D. We show here that evolutionarily divergent retroviruses exhibit distinct integration site profiles with strong preferences for integration near non-canonical B-form DNA (non-B DNA). We also show that in vivo-derived HIV-1 integration sites are significantly more enriched in transcriptionally silent regions and transcription-silencing non-B DNA features of the genome compared to in vitro-derived HIV-1 integration sites. Integration sites from individuals infected with HIV-1 subtype A, B, C or D viruses exhibited different preferences for common genomic and non-B DNA features. In addition, we identified several integration site hotspots shared between different HIV-1 subtypes, all of which were located in the non-B DNA feature slipped DNA. Together, these data show that although evolutionarily divergent retroviruses exhibit distinct integration site profiles, they all target non-B DNA for integration. These findings provide new insight into how retroviruses integrate into genomes for long-term survival. [ABSTRACT FROM AUTHOR]

Both viruses and bacteria produce "pathogen associated molecular patterns" that may affect microbial pathogenesis and anti-microbial responses. Additionally, bacteria produce metabolites, while viruses could change the metabolic profiles of the infected cells. Here, we used an unbiased metabolomics approach to profile metabolites in spleens and blood of murine leukemia virus-infected mice monocolonized with Lactobacillus murinus to show that viral infection significantly changes the metabolite profile of monocolonized mice. We hypothesize that these changes could contribute to viral pathogenesis or to the host response against the virus and thus open a new avenue for future investigations. [ABSTRACT FROM AUTHOR]

After the onset of the AIDS pandemic, HIV-1 (genus Lentivirus) became the predominant model for studying retrovirus Env glycoproteins and their role in entry. However, HIV Env is an inadequate model for understanding entry of viruses in the Alpharetrovirus, Gammaretrovirus and Deltaretrovirus genera. For example, oncogenic model system viruses such as Rous sarcoma virus (RSV, Alpharetrovirus), murine leukemia virus (MLV, Gammaretrovirus) and human T-cell leukemia viruses (HTLV-I and HTLV-II, Deltaretrovirus) encode Envs that are structurally and functionally distinct from HIV Env. We refer to these as Gamma-type Envs. Gamma-type Envs are probably the most widespread retroviral Envs in nature. They are found in exogenous and endogenous retroviruses representing a broad spectrum of vertebrate hosts including amphibians, birds, reptiles, mammals and fish. In endogenous form, gamma-type Envs have been evolutionarily coopted numerous times, most notably as placental syncytins (e.g., human SYNC1 and SYNC2). Remarkably, gamma-type Envs are also found outside of the Retroviridae. Gp2 proteins of filoviruses (e.g., Ebolavirus) and snake arenaviruses in the genus Reptarenavirus are gamma-type Env homologs, products of ancient recombination events involving viruses of different Baltimore classes. Distinctive hallmarks of gamma-type Envs include a labile disulfide bond linking the surface and transmembrane subunits, a multi-stage attachment and fusion mechanism, a highly conserved (but poorly understood) "immunosuppressive domain", and activation by the viral protease during virion maturation. Here, we synthesize work from diverse retrovirus model systems to illustrate these distinctive properties and to highlight avenues for further exploration of gamma-type Env structure and function. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus type 1 (HIV-1) and human T-lymphotropic virus type I (HTLV-I) are two retroviruses that have a similar fashion of transmission via sharp objects contaminated by viruses, transplant surgery, transfusion, and sexual relations. Simultaneous infections with HTLV-I and HIV-1 usually occur in areas where both viruses have become endemic. CD 4 + T cells are the main targets of HTLV-I, while HIV-1 can infect CD 4 + T cells and macrophages. It is the aim of this study to develop a model of HTLV-I and HIV-1 coinfection that describes the interactions of nine compartments: susceptible cells of both CD 4 + T cells and macrophages, HIV-1-infected cells that are latent/active in both CD 4 + T cells and macrophages, HTLV-I-infected CD 4 + T cells that are latent/active, and free HIV-1 particles. The well-posedness, existence of equilibria, and global stability analysis of our model are investigated. The Lyapunov function and LaSalle's invariance principle were used to study the global asymptotic stability of all equilibria. The theoretically predicted outcomes were verified by utilizing numerical simulations. The effect of including the macrophages and latent reservoirs in the HTLV-I and HIV-1 coinfection model is discussed. We show that the presence of macrophages makes a coinfection model more realistic when the case of the coexistence of HIV-1 and HTLV-I is established. Moreover, we have shown that neglecting the latent reservoirs in HTLV-I and HIV-1 coinfection modeling will lead to the design of an overflow of anti-HIV-1 drugs. [ABSTRACT FROM AUTHOR]

Viral quasispecies are distinct but closely related mutants formed by the disparity in viral genomes due to recombination, mutations, competition, and selection pressure. Theoretical derivation for the origin of a quasispecies is owed to the error-prone replication by polymerase and mutants of RNA replicators. Here, we briefly addressed the theoretical and mathematical origin of quasispecies and their dynamics. The impact of quasispecies for major salient human pathogens is reviewed. In the current global scenario, rapid changes in geographical landscapes favor the origin and selection of mutants. It comes as no surprise that a cauldron of mutants poses a significant risk to public health, capable of causing pandemics. Mutation rates in RNA viruses are magnitudes higher than in DNA organisms, explaining their enhanced virulence and evolvability. RNA viruses cause the most devastating pandemics; for example, members of the Orthomyxoviridae family caused the great influenza pandemic (1918 flu or Spanish flu), the SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome) outbreak, and the human immunodeficiency viruses (HIV), lentiviruses of the Retroviridae family, caused worldwide devastation. Rapidly evolving RNA virus populations are a daunting challenge for the designing of effective control measures like vaccines. Developing awareness of the evolutionary dispositions of RNA viral mutant spectra and what influences their adaptation and virulence will help curtail outbreaks of past and future pathogens. [ABSTRACT FROM AUTHOR]

Simple Summary: Pediatric sarcomas, including Ewing sarcoma and osteosarcoma, were first to be treated with an anticancer vaccine 100 years ago. This review moves on from a historical perspective to the current progress and challenges of immunotherapy in these immunologically cold bone and soft tissue sarcomas. We discuss mechanisms of immune escape and immunosuppression employed by these tumors, and the potential novel directions of the research and therapy. The intention of this review is to stimulate alternative concepts and treatment strategies. We argue here that in many ways, Ewing sarcoma (EwS) is a unique tumor entity and yet, it shares many commonalities with other immunologically cold solid malignancies. From the historical perspective, EwS, osteosarcoma (OS) and other bone and soft-tissue sarcomas were the first types of tumors treated with the immunotherapy approach: more than 100 years ago American surgeon William B. Coley injected his patients with a mixture of heat-inactivated bacteria, achieving survival rates apparently higher than with surgery alone. In contrast to OS which exhibits recurrent somatic copy-number alterations, EwS possesses one of the lowest mutation rates among cancers, being driven by a single oncogenic fusion protein, most frequently EWS-FLI1. In spite these differences, both EwS and OS are allied with immune tolerance and low immunogenicity. We discuss here the potential mechanisms of immune escape in these tumors, including low representation of tumor-specific antigens, low expression levels of MHC-I antigen-presenting molecules, accumulation of immunosuppressive M2 macrophages and myeloid proinflammatory cells, and release of extracellular vesicles (EVs) which are capable of reprogramming host cells in the tumor microenvironment and systemic circulation. We also discuss the vulnerabilities of EwS and OS and potential novel strategies for their targeting. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) pandemic is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, which is defined by its positive-sense single-stranded RNA (ssRNA) structure. It is in the order Nidovirales, suborder Coronaviridae, genus Betacoronavirus, and sub-genus Sarbecovirus (lineage B), together with two bat-derived strains with a 96% genomic homology with other bat coronaviruses (BatCoVand RaTG13). Thus far, two Alphacoronavirus strains, HCoV-229E and HCoV-NL63, along with five Betacoronaviruses, HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and SARS-CoV-2, have been recognized as human coronaviruses (HCoVs). SARS-CoV-2 has resulted in more than six million deaths worldwide since late 2019. The appearance of this novel virus is defined by its high and variable transmission rate (RT) and coexisting asymptomatic and symptomatic propagation within and across animal populations, which has a longer-lasting impact. Most current therapeutic methods aim to reduce the severity of COVID-19 hospitalization and virus symptoms, preventing the infection from progressing from acute to chronic in vulnerable populations. Now, pharmacological interventions including vaccines and others exist, with research ongoing. The only ethical approach to developing herd immunity is to develop and provide vaccines and therapeutics that can potentially improve on the innate and adaptive system responses at the same time. Therefore, several vaccines have been developed to provide acquired immunity to SARS-CoV-2 induced COVID-19-disease. The initial evaluations of the COVID-19 vaccines began in around 2020, followed by clinical trials carried out during the pandemic with ongoing population adverse effect monitoring by respective regulatory agencies. Therefore, durability and immunity provided by current vaccines requires further characterization with more extensive available data, as is presented in this paper. When utilized globally, these vaccines may create an unidentified pattern of antibody responses or memory B and T cell responses that need to be further researched, some of which can now be compared within laboratory and population studies here. Several COVID-19 vaccine immunogens have been presented in clinical trials to assess their safety and efficacy, inducing cellular antibody production through cellular B and T cell interactions that protect against infection. This response is defined by virus-specific antibodies (anti-N or anti-S antibodies), with B and T cell characterization undergoing extensive research. In this article, we review four types of contemporary COVID-19 vaccines, comparing their antibody profiles and cellular aspects involved in coronavirus immunology across several population studies. [ABSTRACT FROM AUTHOR]

Acquired Immunodeficiency Syndrome (AIDS) is a human viral infectious disease caused by the positive-sense single-stranded (ss) RNA Human Immunodeficiency Virus (HIV) (Retroviridae family, Ortervirales order). HIV-1 can be distinguished into various worldwide spread groups and subtypes. HIV-2 also causes human immunodeficiency, which develops slowly and tends to be less aggressive. HIV-2 only partially homologates to HIV-1 despite the similar derivation. Antiretroviral therapy (ART) is the treatment approved to control HIV infection, based on multiple antiretroviral drugs that belong to different classes: (i) NNRTIs, (ii) NRTIs, (iii) PIs, (iv) INSTIs, and (v) entry inhibitors. These drugs, acting on different stages of the HIV life cycle, decrease the patient's total burden of HIV, maintain the function of the immune system, and prevent opportunistic infections. The appearance of several strains resistant to these drugs, however, represents a problem today that needs to be addressed as best as we can. New outbreaks of strains show a widespread geographic distribution and a highly variable mortality rate, even affecting treated patients significantly. Therefore, novel treatment approaches should be explored. The present review discusses updated information on HIV-1– and HIV-2–resistant strains, including details on different mutations responsible for drug resistance. [ABSTRACT FROM AUTHOR]

Simple Summary: A unique gene therapy strategy based on tumor-selectively replicating retroviral vectors has shown promising results in clinical trials for glioma and gastrointestinal cancers. Here, we applied this strategy to the treatment of lung cancer, the leading cause of cancer deaths worldwide. Our results demonstrate that retroviral replicating vectors can achieve highly efficient delivery of reporter genes and prodrug activator genes to lung cancer cells in vitro and in vivo, with the latter enabling highly effective cancer cell killing upon exposure to prodrug, achieving significant therapeutic benefit in both subcutaneous and orthotopic pleural dissemination models of lung cancer. Retroviral replicating vector-based gene therapy thus represents a novel strategy with potential to address the unmet medical need for more effective ways to treat lung cancer. Therapeutic efficacy of retroviral replicating vector (RRV)-mediated prodrug activator gene therapy has been demonstrated in a variety of tumor models, but clinical investigation of this approach has so far been restricted to glioma and gastrointestinal malignancies. In the present study, we evaluated replication kinetics, transduction efficiency, and therapeutic efficacy of RRV in experimental models of lung cancer. RRV delivering GFP as a reporter gene showed rapid viral replication in a panel of lung cancer cells in vitro, as well as robust intratumoral replication and high levels of tumor transduction in subcutaneous and orthotopic pleural dissemination models of lung cancer in vivo. Toca 511 (vocimagene amiretrorepvec), a clinical-stage RRV encoding optimized yeast cytosine deaminase (yCD) which converts the prodrug 5-fluorocytosine (5-FC) to the active drug 5-fluorouracil (5-FU), showed potent cytotoxicity in lung cancer cells upon exposure to 5-FC prodrug. In vivo, Toca 511 achieved significant tumor growth inhibition following 5-FC treatment in subcutaneous and orthotopic pleural dissemination models of lung cancer in both immunodeficient and immunocompetent hosts, resulting in significantly increased overall survival. This study demonstrates that RRV can serve as highly efficient vehicles for gene delivery to lung cancer, and indicates the translational potential of RRV-mediated prodrug activator gene therapy with Toca 511/5-FC as a novel therapeutic strategy for pulmonary malignancies. [ABSTRACT FROM AUTHOR]

Synergism between avian leukosis virus subgroup J (ALV-J) and reticuloendotheliosis virus (REV) has been reported frequently in co-infected chicken flocks. Although significant progress has been made in understanding the tumorigenesis mechanisms of ALV and REV, how these two simple oncogenic retroviruses induce synergistic oncogenicity remains unclear. In this study, we found that ALV-J and REV synergistically promoted mutual replication, suppressed cellular senescence, and activated epithelial-mesenchymal transition (EMT) in vitro. Mechanistically, structural proteins from ALV-J and REV synergistically activated the expression of Musashi-1(MSI1), which directly targeted pri-miR-147 through its RNA binding site. This inhibited the maturation of miR-147, which relieved the inhibition of NF-κB/KIAA1199/EGFR signaling, thereby suppressing cellular senescence and activating EMT. We revealed a synergistic oncogenicity mechanism induced by ALV-J and REV in vitro. The elucidation of the synergistic oncogenicity of these two simple retroviruses could help in understanding the mechanism of tumorigenesis in ALV-J and REV co-infection and help identify promising molecular targets and key obstacles for the joint control of ALV-J and REV and the development of clinical technologies. [ABSTRACT FROM AUTHOR]

The bovine leukemia virus (BLV) and the human T-lymphothropic viruses (HTLVs) are members of the deltaretrovirus genus of Retroviridae family. An essential event of the retroviral life cycle is the processing of the polyproteins by the viral protease (PR); consequently, these enzymes became important therapeutic targets of the anti-retroviral drugs. As compared to human immunodeficiency viruses (HIVs), the deltaretroviruses have a different replication strategy, as they replicate predominantly in the DNA form, by forcing the infected cell to divide, unlike HIV-1, which replicates mainly by producing a vast number of progeny virions and by reinfection. Due to bypassing the error-prone reverse transcription step of replication, the PRs of deltaretroviruses did not undergo such extensive evolution as HIV PRs and remained more highly conserved. In this work, we studied the abilities of wild-type and modified BLV, HTLV (type 1, 2 and 3), and HIV-1 PRs (fused to an N-terminal MBP tag) for self-processing. We designed a cleavage site mutant MBP-fused BLV PR precursor as well, this recombinant enzyme was unable for self-proteolysis, the MBP fusion tag decreased its catalytic efficiency but showed an unusually low Ki for the IB-268 protease inhibitor. Our results show that the HTLV and BLV deltaretrovirus PRs exhibit lower mutation tolerance as compared to HIV-1 PR, and are less likely to retain their activity upon point mutations at various positions, indicating a higher flexibility of HIV-1 PR in tolerating mutations under selective pressure. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus type 1 (HIV-1) and human T-lymphotropic virus type I (HTLV-I) are two retroviruses which infect the same target, CD 4 + T cells. This type of cell is considered the main component of the immune system. Since both viruses have the same means of transmission between individuals, HIV-1-infected patients are more exposed to the chance of co-infection with HTLV-I, and vice versa, compared to the general population. The mathematical modeling and analysis of within-host HIV-1/HTLV-I co-infection dynamics can be considered a robust tool to support biological and medical research. In this study, we have formulated and analyzed an HIV-1/HTLV-I co-infection model with humoral immunity, taking into account both latent HIV-1-infected cells and HTLV-I-infected cells. The model considers two modes of HIV-1 dissemination, virus-to-cell (V-T-C) and cell-to-cell (C-T-C). We prove the nonnegativity and boundedness of the solutions of the model. We find all steady states of the model and establish their existence conditions. We utilize Lyapunov functions and LaSalle's invariance principle to investigate the global stability of all the steady states of the model. Numerical simulations were performed to illustrate the corresponding theoretical results. The effects of humoral immunity and C-T-C transmission on the HIV-1/HTLV-I co-infection dynamics are discussed. We have shown that humoral immunity does not play the role of clearing an HIV-1 infection but it can control HIV-1 infection. Furthermore, we note that the omission of C-T-C transmission from the HIV-1/HTLV-I co-infection model leads to an under-evaluation of the basic HIV-1 mono-infection reproductive ratio. [ABSTRACT FROM AUTHOR]

Retroviral integrase is a multimeric enzyme that catalyzes the integration of reverse-transcribed viral DNA into the cellular genome. Beyond integration, the Human immunodeficiency virus type 1 (HIV-1) integrase is also involved in many other steps of the viral life cycle, such as reverse transcription, nuclear import, virion morphogenesis and proviral transcription. All these additional functions seem to depend on the action of the integrase C-terminal domain (CTD) that works as a molecular hub, interacting with many different viral and cellular partners. In this review, we discuss structural issues concerning the CTD, with particular attention paid to its interaction with nucleic acids. We also provide a detailed map of post-translational modifications and interaction with molecular partners. [ABSTRACT FROM AUTHOR]

Simple Summary: The v-raf murine sarcoma viral oncogene homolog B1 (BRAF) gene containing a 15-base pair (bp) deletion at L485-P490 is the cause of several cancers. We generated siRNA to specifically knock down BRAF mRNA containing the 15-bp deletion. This siRNA suppressed the expression of BRAF, harboring the deletion without affecting wild-type BRAF expression in BxPC-3 pancreatic ductal adenocarcinoma cells in vitro and in vivo. Cell growth and phosphorylation of downstream extracellular-signal-regulated kinase proteins were also repressed. An off-target effect is the most common side effect of siRNA therapy. In this study, we reveal that siRNA with a 2′-O-methyl chemical modification in the seed region of the siRNA guide strand reduced seed-dependent off-target effects. Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second-most common cause of death within the next 10 years. Due to the limited efficacy of available therapies, the survival rate of PDAC patients is very low. Oncogenic BRAF mutations are one of the major causes of PDAC, specifically the missense V600E and L485–P490 15-bp deletion mutations. Drugs targeting the V600E mutation have already been approved by the United States Food and Drug Administration. However, a drug targeting the deletion mutation at L485–P490 of the BRAF gene has not been developed to date. The BxPC-3 cell line is a PDAC-derived cell line harboring wild-type KRAS and L485–P490 deleted BRAF genes. These cells are heterozygous for BRAF, harboring both wild-type BRAF and BRAF with the 15-bp deletion. In this study, siRNA was designed for the targeted knockdown of 15-bp deletion-type BRAF mRNA. This siRNA repressed the phosphorylation of extracellular-signal-regulated kinase proteins downstream of BRAF and suppressed cell growth in vitro and in vivo. Furthermore, siRNAs with 2′-O-methyl modifications at positions 2–5 reduce the seed-dependent off-target effects, as confirmed by reporter and microarray analyses. Thus, such siRNA is a promising candidate therapy for 15-bp deletion-type BRAF-induced tumorigenesis. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic ductal adenocarcinoma (PDAC) is a common type of cancer originating from the pancreatic glands and is characterized by a rapidly progressive course and a dismal prognosis. Currently, chemotherapy is the cornerstone of treatment that has modest efficacy. Targeted treatment options are rapidly evolving with the growing understanding of pathobiological underpinnings of tumorigenesis, progression, and treatment resistance mechanisms. Combination strategies targeting multiple signaling pathways supporting tumor growth and propagation are active areas of contemporary research that will likely transform the treatment paradigm of pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by nonspecific presenting symptoms, lack of a screening test, rapidly progressive clinical course, and presentation with an advanced-stage disease in the majority of patients. PDAC is essentially a systemic disease irrespective of the initial stage, as most patients with non-metastatic PDAC undergoing curative-intent treatment eventually experience metastatic relapse. Currently, cytotoxic chemotherapy remains the cornerstone of treatment in patients with advanced disease. However, the current standard treatment with multiagent chemotherapy has modest efficacy and results in median overall survival (OS) of less than a year and a 5-year OS of about 10%. The pathobiology of PDAC poses many challenges, including a unique tumor microenvironment interfering with drug delivery, intratumoral heterogeneity, and a strongly immunosuppressive microenvironment that supports cancer growth. Recent research is exploring a wide range of novel therapeutic targets, including genomic alterations, tumor microenvironment, and tumor metabolism. The rapid evolution of tumor genome sequencing technologies paves the way for personalized, targeted therapies. The present review summarizes the current chemotherapeutic treatment paradigm of advanced PDAC and discusses the evolving novel targets that are being investigated in a myriad of clinical trials. [ABSTRACT FROM AUTHOR]

This review is an accompaniment to a Special Issue on "Retroviral RNA Processing". It discusses post-transcriptional regulation of retroviruses, ranging from the ancient foamy viruses to more modern viruses, such as HIV-1, HTLV-1, Rous sarcoma virus, murine leukemia virus, mouse mammary tumor virus, and Mason-Pfizer monkey virus. This review is not comprehensive. However, it tries to address some of the major questions in the field with examples of how different retroviruses express their genes. It is amazing that a single primary RNA transcript can have so many possible fates: genomic RNA, unspliced mRNA, and up to 50 different alternatively spliced mRNAs. This review will discuss the sorting of RNAs for packaging or translation, RNA nuclear export mechanisms, splicing, translation, RNA modifications, and avoidance of nonsense-mediated RNA decay. [ABSTRACT FROM AUTHOR]

Lamellarin α 20-sulfate is a cell-impenetrable marine alkaloid that can suppress infection that is mediated by the envelope glycoprotein of human immunodeficiency virus type 1. We explored the antiviral action and mechanisms of this alkaloid against emerging enveloped RNA viruses that use endocytosis for infection. The alkaloid inhibited the infection of retroviral vectors that had been pseudotyped with the envelope glycoprotein of Ebola virus and SARS-CoV-2. The antiviral effects of lamellarin were independent of the retrovirus Gag-Pol proteins. Interestingly, although heparin and dextran sulfate suppressed the cell attachment of vector particles, lamellarin did not. In silico structural analyses of the trimeric glycoprotein of the Ebola virus disclosed that the principal lamellarin-binding site is confined to a previously unappreciated cavity near the NPC1-binding site and fusion loop, whereas those for heparin and dextran sulfate were dispersed across the attachment and fusion subunits of the glycoproteins. Notably, lamellarin binding to this cavity was augmented under conditions where the pH was 5.0. These results suggest that the final action of the alkaloid against Ebola virus is specific to events following endocytosis, possibly during conformational glycoprotein changes in the acidic environment of endosomes. Our findings highlight the unique biological and physicochemical features of lamellarin α 20-sulfate and should lead to the further use of broadly reactive antivirals to explore the structural mechanisms of virus replication. [ABSTRACT FROM AUTHOR]