-
Frontiers in Immunology 2019Vaccines can successfully prevent viral infections and have emerged as an effective strategy for preventing some virally mediated malignancies. They also represent our... (Review)
Review
Vaccines can successfully prevent viral infections and have emerged as an effective strategy for preventing some virally mediated malignancies. They also represent our major hope for cost-effective reduction of the cancer burden. The concept that the immune system mediates surveillance and editing roles against tumors is now well-established in murine models. However, harnessing the immune system to prevent human cancers that do not have a known viral etiology has not yet been realized. Most human cancers originate in a premalignant phase that is more common than the cancer itself. Many of the genetic changes that underlie carcinogenesis originate at this stage when the malignant phenotype is not manifest. Studies evaluating host response in human premalignancy have documented that these lesions are immunogenic, setting the stage for immune-based approaches for targeted prevention of human cancer. However, recent studies suggest that the hierarchy of T cell exhaustion and immune-suppressive factors have already begun to emerge in many preneoplastic states. These considerations underscore the need to link immune prevention to earlier detection of such lesions and to personalize such approaches based on the status of the pre-existing immune response.
Topics: Animals; Antigens, Neoplasm; Cancer Vaccines; Cell Transformation, Viral; Chronic Disease; Clinical Trials as Topic; Disease Models, Animal; Disease Susceptibility; Early Detection of Cancer; Humans; Immunologic Surveillance; Immunotherapy; Mutation; Neoplasms; Precancerous Conditions; T-Lymphocytes; Treatment Outcome; Virus Diseases
PubMed: 31649683
DOI: 10.3389/fimmu.2019.02385 -
AIDS (London, England) Mar 2020To describe viral load levels among pregnant women and factors associated with failure to achieve viral suppression (viral load ≤50 copies/ml) during pregnancy.
OBJECTIVE
To describe viral load levels among pregnant women and factors associated with failure to achieve viral suppression (viral load ≤50 copies/ml) during pregnancy.
DESIGN
Between 1 October and 15 November 2017, a cross-sectional survey was conducted among 15-49-year-old pregnant women attending antenatal care (ANC) at 1595 nationally representative public facilities.
METHODS
Blood specimens were taken from each pregnant woman and tested for HIV. Viral load testing was done on all HIV-positive specimens. Demographic and clinical data were extracted from medical records or self-reported. Survey logistic regression examined factors associated with failure to achieve viral suppression.
RESULT
Of 10 052 HIV-positive participants with viral load data, 56.2% were virally suppressed. Participants initiating antiretroviral therapy (ART) prior to pregnancy had higher viral suppression (71.0%) by their third trimester compared with participants initiating ART during pregnancy (59.3%). Booking for ANC during the third trimester vs. earlier: [adjusted odds ratio (AOR) 1.8, 95% confidence interval (CI):1.4-2.3], low frequency of ANC visits (AOR for 2 ANC visits vs. ≥4 ANC visits: 2.0, 95% CI:1.7-2.4), delayed initiation of ART (AOR for ART initiated at the second trimester vs. before pregnancy:2.2, 95% CI:1.8-2.7), and younger age (AOR for 15-24 vs. 35-49 years: 1.4, 95% CI:1.2-1.8) were associated with failure to achieve viral suppression during the third trimester.
CONCLUSION
Failure to achieve viral suppression was primarily associated with late ANC booking and late initiation of ART. Efforts to improve early ANC booking and early ART initiation in the general population would help improve viral suppression rates among pregnant women. In addition, the study found, despite initiating ART prior to pregnancy, more than one quarter of participants did not achieve viral suppression in their third trimester. This highlights the need to closely monitor viral load and strengthen counselling and support services for ART adherence.
Topics: Adolescent; Adult; Anti-HIV Agents; Cross-Sectional Studies; Female; HIV Infections; Humans; Infectious Disease Transmission, Vertical; Logistic Models; Middle Aged; Pregnancy; Pregnancy Complications, Infectious; Prenatal Care; South Africa; Time Factors; Viral Load; Young Adult
PubMed: 31821189
DOI: 10.1097/QAD.0000000000002457 -
Reviews in Medical Virology Sep 2021Severe acute respiratory syndrome coronavirus-2 is the etiological agent of the ongoing pandemic of coronavirus disease-2019, a multi-organ disease that has triggered an... (Review)
Review
Severe acute respiratory syndrome coronavirus-2 is the etiological agent of the ongoing pandemic of coronavirus disease-2019, a multi-organ disease that has triggered an unprecedented global health and economic crisis. The virally encoded 3C-like protease (3CL ), which is named after picornaviral 3C protease (3C ) due to their similarities in substrate recognition and enzymatic activity, is essential for viral replication and has been considered as the primary drug target. However, information regarding the cellular substrates of 3CL and its interaction with the host remains scarce, though recent work has begun to shape our understanding more clearly. Here we summarized and compared the mechanisms by which picornaviruses and coronaviruses have evolved to evade innate immune surveillance, with a focus on the established role of 3C in this process. Through this comparison, we hope to highlight the potential action and mechanisms that are conserved and shared between 3C and 3CL . In this review, we also briefly discussed current advances in the development of broad-spectrum antivirals targeting both 3C and 3CL .
Topics: Animals; COVID-19; Coronavirus 3C Proteases; Humans; Immune Evasion; Picornaviridae; SARS-CoV-2
PubMed: 33624382
DOI: 10.1002/rmv.2206 -
Reproductive Toxicology (Elmsford, N.Y.) Dec 2022UV-4 (N-(9-methoxynonyl)-1-deoxynojirimycin) is a host-targeted antiviral agent, which targets mammalian proteins (endoplasmic reticulum glucosidases) rather than...
UV-4 (N-(9-methoxynonyl)-1-deoxynojirimycin) is a host-targeted antiviral agent, which targets mammalian proteins (endoplasmic reticulum glucosidases) rather than virally encoded proteins. This mechanism confers both broad-spectrum activity and low potential for generation of viral drug resistance mutations. Reproductive and developmental studies of UV-4 evaluated effects on fertility and early embryonic development in rats, embryo-fetal development in rats and rabbits, and pre- and postnatal development including maternal function in rats. All reproductive and developmental studies conducted achieved dose levels where parental toxicity (generally decreased body weight, decreased food consumption and adverse clinical signs) were observed. Toxicokinetic evaluations confirmed UV-4 crossed the placenta exposing fetal rats and rabbits in utero. Adverse findings in reproductive and developmental studies included decreases in sperm motility with histopathology correlates, visceral and skeletal malformations, changes in eye opening, air drop reflex, vaginal opening and preputial separation. The combined results of the fertility and early embryonic developmental study and pre- and postnatal study suggested that there may be an increased risk for male fertility. These effects are similar to those reported in pre-clinical studies of the structurally related drug Miglustat (N-butyl-1-deoxynojirimycin), therefore UV-4 may have risk of developmental or reproductive adverse outcomes in humans similar to existing approved agents in this drug class.
Topics: Pregnancy; Female; Humans; Male; Rats; Rabbits; Animals; Rats, Sprague-Dawley; Dose-Response Relationship, Drug; Sperm Motility; Reproduction; Fertility; Body Weight; Mammals
PubMed: 36206921
DOI: 10.1016/j.reprotox.2022.09.007 -
Journal of the International... 2022The Dominican Republic (DR) has the second-highest prevalence of HIV infection in the Caribbean, but viral suppression and treatment adherence are not well understood....
The Dominican Republic (DR) has the second-highest prevalence of HIV infection in the Caribbean, but viral suppression and treatment adherence are not well understood. We conducted a cross-sectional study among people living with HIV/AIDS(PLWHA) to fill in the knowledge gap. Questionnaire was used to collect demographic data, antiretroviral therapy (ART) adherence, and barriers and facilitators to HIV care. Viral load and other clinical information were extracted through chart reviews. Descriptive analyzes and logistic regression were conducted to explore factors associated with non-viral suppression and imperfect ART adherence. Of 193 PLWHA 83.9% were virally suppressed. Those that were non-virally suppressed were more likely of being male (odds ratio [OR]: 2.55, 95% confidence interval [CI]: 1.17-5.58) and less likely of being unemployed (OR: 0.28, 95% CI: 0.08-0.96). However, being male (OR: 0.78, 95% CI:0.40-1.53) and unemployed (OR: 0.28, 95% CI:0. 08-1.21) were less likely to report imperfect adherence. Tailored interventions are needed to improve adherence and viral suppression in DR.
Topics: Anti-HIV Agents; Anti-Retroviral Agents; Cross-Sectional Studies; Dominican Republic; Female; HIV Infections; Humans; Male; Medication Adherence; Viral Load
PubMed: 35532067
DOI: 10.1177/23259582221096522 -
Current Opinion in Virology Aug 2021Bacterial communities play critical roles across all of Earth's biomes, affecting human health and global ecosystem functioning. They do so under strong constraints... (Review)
Review
Bacterial communities play critical roles across all of Earth's biomes, affecting human health and global ecosystem functioning. They do so under strong constraints exerted by viruses, that is, bacteriophages or 'phages'. Phages can reshape bacterial communities' structure, influence long-term evolution of bacterial populations, and alter host cell metabolism during infection. Metagenomics approaches, that is, shotgun sequencing of environmental DNA or RNA, recently enabled large-scale exploration of phage genomic diversity, yielding several millions of phage genomes now to be further analyzed and characterized. One major challenge however is the lack of direct host information for these phages. Several methods and tools have been proposed to bioinformatically predict the potential host(s) of uncultivated phages based only on genome sequence information. Here we review these different approaches and highlight their distinct strengths and limitations. We also outline complementary experimental assays which are being proposed to validate and refine these bioinformatic predictions.
Topics: Bacteria; Bacteriophages; Base Sequence; Computational Biology; Computer Simulation; Genes, Viral; Genome, Bacterial; Genome, Viral; Host Microbial Interactions; Host Specificity; Machine Learning; Metagenomics; Phylogeny; Viral Proteins; Virology
PubMed: 34126465
DOI: 10.1016/j.coviro.2021.05.003 -
Cell Reports May 2023Upon recognizing danger signals produced by virally infected neurons, macrophages in the central nervous system (CNS) secrete multiple inflammatory cytokines to...
Upon recognizing danger signals produced by virally infected neurons, macrophages in the central nervous system (CNS) secrete multiple inflammatory cytokines to accelerate neuron apoptosis. The understanding is limited about which key effectors regulate macrophage-neuron crosstalk upon infection. We have used neurotropic-virus-infected murine models to identify that vascular endothelial growth factor receptor 3 (VEGFR-3) is upregulated in the CNS macrophages and that virally infected neurons secrete the ligand VEGF-C. When cultured with VEGF-C-containing supernatants from virally infected neurons, VEGFR-3 macrophages suppress tumor necrosis factor α (TNF-α) secretion to reduce neuron apoptosis. Vegfr-3 (deletion of ligand-binding domain in myeloid cells) mice or mice treated with the VEGFR-3 kinase inhibitor exacerbate the severity of encephalitis, TNF-α production, and neuron apoptosis post Japanese encephalitis virus (JEV) infection. Activating VEGFR-3 or blocking TNF-α can reduce encephalitis and neuronal damage upon JEV infection. Altogether, we show that the inducible VEGF-C/VEGFR-3 module generates protective crosstalk between neurons and macrophages to alleviate CNS viral infection.
Topics: Mice; Animals; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor Receptor-3; Vascular Endothelial Growth Factor C; Ligands; Vascular Endothelial Growth Factor A; Encephalitis, Japanese; Encephalitis Virus, Japanese; Neurons; Macrophages
PubMed: 37167063
DOI: 10.1016/j.celrep.2023.112489 -
Viruses Jan 2021Viral dysregulation or suppression of innate immune responses is a key determinant of virus-induced pathogenesis. Important sensors for the detection of virus infection... (Review)
Review
Viral dysregulation or suppression of innate immune responses is a key determinant of virus-induced pathogenesis. Important sensors for the detection of virus infection are the RIG-I-like receptors (RLRs), which, in turn, are antagonized by many RNA viruses and DNA viruses. Among the different escape strategies are viral mechanisms to dysregulate the post-translational modifications (PTMs) that play pivotal roles in RLR regulation. In this review, we present the current knowledge of immune evasion by viral pathogens that manipulate ubiquitin- or ISG15-dependent mechanisms of RLR activation. Key viral strategies to evade RLR signaling include direct targeting of ubiquitin E3 ligases, active deubiquitination using viral deubiquitinating enzymes (DUBs), and the upregulation of cellular DUBs that regulate RLR signaling. Additionally, we summarize emerging new evidence that shows that enzymes of certain coronaviruses such as SARS-CoV-2, the causative agent of the current COVID-19 pandemic, actively deISGylate key molecules in the RLR pathway to escape type I interferon (IFN)-mediated antiviral responses. Finally, we discuss the possibility of targeting virally-encoded proteins that manipulate ubiquitin- or ISG15-mediated innate immune responses for the development of new antivirals and vaccines.
Topics: Coronavirus 3C Proteases; Cytokines; DEAD Box Protein 58; Humans; Immune Evasion; Immunity, Innate; Receptors, Immunologic; SARS-CoV-2; Signal Transduction; Ubiquitin; Ubiquitins; Virus Diseases; Viruses
PubMed: 33530371
DOI: 10.3390/v13020182 -
Virology Journal Jan 2020Viruses are the most numerous entities on Earth and have also been central to many episodes in the history of humankind. As the study of viruses progresses further and...
BACKGROUND
Viruses are the most numerous entities on Earth and have also been central to many episodes in the history of humankind. As the study of viruses progresses further and further, there are several limitations in transferring this knowledge to undergraduate and high school students. This deficiency is due to the difficulty in designing hands-on lessons that allow students to better absorb content, given limited financial resources and facilities, as well as the difficulty of exploiting viral particles, due to their small dimensions. The development of tools for teaching virology is important to encourage educators to expand on the covered topics and connect them to recent findings. Discoveries, such as giant DNA viruses, have provided an opportunity to explore aspects of viral particles in ways never seen before. Coupling these novel findings with techniques already explored by classical virology, including visualization of cytopathic effects on permissive cells, may represent a new way for teaching virology. This work aimed to develop a slide microscope kit that explores giant virus particles and some aspects of animal virus interaction with cell lines, with the goal of providing an innovative approach to virology teaching.
METHODS
Slides were produced by staining, with crystal violet, purified giant viruses and BSC-40 and Vero cells infected with viruses of the genera Orthopoxvirus, Flavivirus, and Alphavirus. Slides with amoebae infected with different species of giant viruses and stained with hemacolor reagents were also produced.
RESULTS
Staining of the giant viruses allowed better visualization of the viral particles, and this technique highlights the diversity in morphology and sizes among them. Hemacolor staining enabled visualization of viral factories in amoebae, and the staining of infected BSC-40 and Vero cell monolayers with crystal violet highlights plaque-forming units.
CONCLUSIONS
This kit was used in practical virology classes for the Biological Sciences course (UFMG, Brazil), and it will soon be made available at a low-cost for elementary school teachers in institutions that have microscopes. We hope this tool will foster an inspiring learning environment.
Topics: Animals; Cell Line; Chlorocebus aethiops; Giant Viruses; Humans; Microscopy; Students; Teaching; Teaching Materials; Vero Cells; Virology; Viruses
PubMed: 32005257
DOI: 10.1186/s12985-020-1291-9 -
Journal of Virology Oct 2023This study highlights the crucial role RNA processing plays in regulating viral gene expression and replication. By targeting SR kinases, we identified harmine as a...
This study highlights the crucial role RNA processing plays in regulating viral gene expression and replication. By targeting SR kinases, we identified harmine as a potent inhibitor of HIV-1 as well as coronavirus (HCoV-229E and multiple SARS-CoV-2 variants) replication. Harmine inhibits HIV-1 protein expression and reduces accumulation of HIV-1 RNAs in both cell lines and primary CD4 T cells. Harmine also suppresses coronavirus replication post-viral entry by preferentially reducing coronavirus sub-genomic RNA accumulation. By focusing on host factors rather than viral targets, our study offers a novel approach to combating viral infections that is effective against a range of unrelated viruses. Moreover, at doses required to inhibit virus replication, harmine had limited toxicity and minimal effect on the host transcriptome. These findings support the viability of targeting host cellular processes as a means of developing broad-spectrum anti-virals.
Topics: Humans; Antiviral Agents; Coronavirus; Coronavirus Infections; Harmine; HIV-1; Virus Replication
PubMed: 37706687
DOI: 10.1128/jvi.00396-23