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Journal of Molecular Biology Jun 2024A large body of work in the last four decades has revealed the key pillars of HIV-1 transcription control at the initiation and elongation steps. Here, I provide a... (Review)
Review
A large body of work in the last four decades has revealed the key pillars of HIV-1 transcription control at the initiation and elongation steps. Here, I provide a recount of this collective knowledge starting with the genomic elements (DNA and nascent TAR RNA stem-loop) and transcription factors (cellular and the viral transactivator Tat), and later transitioning to the assembly and regulation of transcription initiation and elongation complexes, and the role of chromatin structure. Compelling evidence support a core HIV-1 transcriptional program regulated by the sequential and concerted action of cellular transcription factors and Tat to promote initiation and sustain elongation, highlighting the efficiency of a small virus to take over its host to produce the high levels of transcription required for viral replication. I summarize new advances including the use of CRISPR-Cas9, genetic tools for acute factor depletion, and imaging to study transcriptional dynamics, bursting and the progression through the multiple phases of the transcriptional cycle. Finally, I describe current challenges to future major advances and discuss areas that deserve more attention to both bolster our basic knowledge of the core HIV-1 transcriptional program and open up new therapeutic opportunities.
PubMed: 38936695
DOI: 10.1016/j.jmb.2024.168690 -
Molecular Metabolism Jun 2024The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) continues to rise with the increasing obesity epidemic. Rezdiffra as an activator of a...
OBJECTIVE
The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) continues to rise with the increasing obesity epidemic. Rezdiffra as an activator of a thyroid hormone receptor-beta is the only Food and Drug Administration approved therapy. As such, there is a critical need to improve our understanding of gene expression regulation and signaling transduction in MASLD to develop new therapies. Matrin-3 is a DNA- and RNA-binding protein involved in the pathogenesis of human diseases. Here we examined its previously uncharacterized role in limiting hepatic steatosis and stress response via the constitutive androstane receptor (CAR).
METHODS
Matrin-3 floxed and liver-specific knockout mice were fed either a chow diet or 60 kcal% high-fat diet (HFD) for up to 16 weeks. The mice were euthanized for different analysis including liver histology, lipid levels, and gene expression. Bulk RNA-seq, bulk ATAC-seq, and single-nucleus Multiome were used to examine changes of transcriptome and chromatin accessibility in the liver. Integrative bioinformatics analysis of our data and publicly available datasets and different biochemical assays were performed to identify underlying the molecular mechanisms mediating matrin-3's effects. Liver-tropic adeno-associated virus was used to restore the expression of CAR for lipid, acute phase genes, and histological analysis.
RESULTS
Matrin-3 expression is induced in the steatotic livers of mice. Liver-specific matrin-3 deletion exacerbated HFD-induced steatosis, acute phase response, and inflammation in the liver of female mice. The transcriptome and chromatin accessibility were re-programmed in the liver of these mice with signatures indicating that CAR signaling is dysregulated. Mechanistically, matrin-3 interacts with CAR mRNA, and matrin-3 deficiency promotes CAR mRNA degradation. Consequently, matrin-3 deletion impaired CAR signaling by reducing CAR expression. Matrin-3 levels positively correlate with CAR expression in human livers. Ces2a and Il1r1 were identified as new target genes of CAR. Interestingly, we found that CAR discords with the expression of its target genes including Cyp2b10 and Ces2a in response to HFD, indicating CAR signaling is dysregulated by HFD despite increased CAR expression. Dysregulated CAR signaling upon matrin-3 deficiency reduced Ces2a and de-repressed Il1r1 expression. CAR restoration partially abrogated the dysregulated gene expression, exacerbated hepatic steatosis, acute phase response, and inflammation in liver-specific matrin-3 knockout mice fed a HFD.
CONCLUSIONS
Our findings demonstrate that matrin-3 is a key upstream regulator maintaining CAR signaling upon metabolic stress, and the matrin-3-CAR axis limits hepatic steatosis and stress response signaling that may give insights for therapeutic intervention.
PubMed: 38936659
DOI: 10.1016/j.molmet.2024.101977 -
PloS One 2024Hepatitis B virus (HBV) infection is a global public health issue. We offer a comprehensive analysis of the dynamics of HBV, which can be successfully controlled with...
Hepatitis B virus (HBV) infection is a global public health issue. We offer a comprehensive analysis of the dynamics of HBV, which can be successfully controlled with vaccine and treatment. Hepatitis B virus (HBV) causes a significantly more severe and protracted disease compared to hepatitis A. While it initially presents as an acute disease, in approximately 5 to 10% of cases, it can develop into a chronic disease that causes permanent damage to the liver. The hepatitis B virus can remain active outside the body for at least seven days. If the virus penetrates an individual's body without immunization, it may still result in infection. Upon exposure to HBV, the symptoms often last for a duration ranging from 10 days to 6 months. In this study, we developed a new model for Hepatitis B Virus (HBV) that includes asymptomatic carriers, vaccination, and treatment classes to gain a comprehensive knowledge of HBV dynamics. The basic reproduction number [Formula: see text] is calculated to identify future recurrence. The local and global stabilities of the proposed model are evaluated for values of [Formula: see text] that are both below and above 1. The Lyapunov function is employed to ensure the global stability of the HBV model. Further, the existence and uniqueness of the proposed model are demonstrated. To look at the solution of the proposed model graphically, we used a useful numerical strategy, such as the non-standard finite difference method, to obtain more thorough numerical findings for the parameters that have a significant impact on disease elimination. In addition, the study of treatment class in the population, we may assess the effectiveness of alternative medicines to treat infected populations can be determined. Numerical simulations and graphical representations are employed to illustrate the implications of our theoretical conclusions.
Topics: Humans; Hepatitis B; Hepatitis B virus; Computer Simulation; Epidemics; Hepatitis B Vaccines; Basic Reproduction Number; Vaccination
PubMed: 38935766
DOI: 10.1371/journal.pone.0304375 -
Clinical and Translational Medicine Jul 2024Hepatitis B virus (HBV) infection playsa significant role in the etiology and progression of liver-relatedpathologies, encompassing chronic hepatitis, fibrosis,... (Review)
Review
Hepatitis B virus (HBV) infection playsa significant role in the etiology and progression of liver-relatedpathologies, encompassing chronic hepatitis, fibrosis, cirrhosis, and eventual hepatocellularcarcinoma (HCC). Notably, HBV infection stands as the primary etiologicalfactor driving the development of HCC. Given the significant contribution ofHBV infection to liver diseases, a comprehensive understanding of immunedynamics in the liver microenvironment, spanning chronic HBV infection,fibrosis, cirrhosis, and HCC, is essential. In this review, we focused on thefunctional alterations of CD8 T cells within the pathogenic livermicroenvironment from HBV infection to HCC. We thoroughly reviewed the roles ofhypoxia, acidic pH, metabolic reprogramming, amino acid deficiency, inhibitory checkpointmolecules, immunosuppressive cytokines, and the gut-liver communication in shapingthe dysfunction of CD8 T cells in the liver microenvironment. Thesefactors significantly impact the clinical prognosis. Furthermore, we comprehensivelyreviewed CD8 T cell-based therapy strategies for liver diseases,encompassing HBV infection, fibrosis, cirrhosis, and HCC. Strategies includeimmune checkpoint blockades, metabolic T-cell targeting therapy, therapeuticT-cell vaccination, and adoptive transfer of genetically engineered CD8 T cells, along with the combined usage of programmed cell death protein-1/programmeddeath ligand-1 (PD-1/PD-L1) inhibitors with mitochondria-targeted antioxidants.Given that targeting CD8 T cells at various stages of hepatitis Bvirus-induced hepatocellular carcinoma (HBV + HCC) shows promise, we reviewedthe ongoing need for research to elucidate the complex interplay between CD8 T cells and the liver microenvironment in the progression of HBV infection toHCC. We also discussed personalized treatment regimens, combining therapeuticstrategies and harnessing gut microbiota modulation, which holds potential forenhanced clinical benefits. In conclusion, this review delves into the immunedynamics of CD8 T cells, microenvironment changes, and therapeuticstrategies within the liver during chronic HBV infection, HCC progression, andrelated liver diseases.
Topics: Humans; CD8-Positive T-Lymphocytes; Hepatitis B virus; Hepatitis B, Chronic; Carcinoma, Hepatocellular; Liver Neoplasms; Liver Diseases
PubMed: 38935536
DOI: 10.1002/ctm2.1731 -
Indian Journal of Public Health Oct 2023
Gay and Bisexual Men too should not be Left Out/Deprived of Human Papilloma Virus Vaccination in "Cervical Cancer Elimination Programme" in Countries with a High Prevalence of HIV.
Topics: Humans; Male; Papillomavirus Vaccines; HIV Infections; Uterine Cervical Neoplasms; Papillomavirus Infections; Female; Prevalence; Sexual and Gender Minorities; India; Homosexuality, Male; Human Papillomavirus Viruses
PubMed: 38934843
DOI: 10.4103/ijph.ijph_1646_22 -
Intervirology Jun 2024This study aimed to investigate the differences between pregnant women with chronic hepatitis B virus (HBV) infection and intrafamilial infection and those without...
INTRODUCTION
This study aimed to investigate the differences between pregnant women with chronic hepatitis B virus (HBV) infection and intrafamilial infection and those without intrafamilial infection.
METHODS
HBV DNA was extracted from the sera of 16 pregnant women with chronic hepatitis B (CHB) and their family members for gene sequencing and phylogenetic analyses. A total of 74 pregnant women with CHB were followed up from the second trimester to three months postpartum. Viral markers and other laboratory indicators were compared between pregnant women with CHB with and without intrafamilial infection.
RESULTS
The phylogenetic tree showed that HBV lines in the mother-spread pedigree shared a node, whereas there was an unrelated genetic background for HBV lines in individuals without intrafamilial infection. From delivery to three months postpartum, compared with those without intrafamilial infection, pregnant women with intrafamilial infection were related negatively to HBV DNA (β=-0.43, 95% Confidence Interval [CI]: -0.76 to -0.12, p=0.009), HBeAg (β=-195.15, 95% CI: -366.35 to -23.96, p=0.027), and hemoglobin changes (β=-8.09, 95%CI: -15.54 to -0.64, p=0.035) and positively to changes in the levels of alanine aminotransferase (β=73.9, 95%CI:38.92-108.95, p<0.001) and albumin (β=2.73, 95% CI:0.23-5.23, p=0.033).
CONCLUSION
The mother-spread pedigree spread model differs from that of non-intrafamilial infections. Pregnant women with intra-familial HBV infection have less hepatitis flares and liver damage, but their HBV DNA and HBeAg levels rebound faster after delivery, than those without intra-familial infection by the virus.
PubMed: 38934174
DOI: 10.1159/000539994 -
Vaccines Jun 2024Convalescent plasma has been shown to be effective at protecting humans against severe diseases caused by New World (NW) arenaviruses, including Junin virus (JUNV) and...
Convalescent plasma has been shown to be effective at protecting humans against severe diseases caused by New World (NW) arenaviruses, including Junin virus (JUNV) and Machupo virus (MACV). This plasma contains antibodies against the full complement of structural proteins including the nucleocapsid and envelope glycoproteins (GPcs) consisting of GP1 and GP2. To gain insights into the protective and cross-protective properties of anti-GPc-specific polyclonal antibodies, we evaluated the ability of a DNA vaccine-produced anti-GPc rabbit antisera targeting MACV strain Carvallo to provide heterologous protection against another MACV strain termed Chicava in the Hartley guinea pig model. The neutralizing activity of the rabbit antisera against the heterologous MACV strains Chicava and Mallale was found to be 54-fold and 23-fold lower, respectively, compared to the titer against the homologous MACV strain Carvallo in the PRNT50 assay. Despite lower neutralizing activity against the strain Chicava, the rabbit antisera protected 100% of the guinea pigs from this strain when administered up to four days post-infection, whereas all the control animals succumbed to the disease. Using vesicular stomatitis virus (VSV) particles pseudotyped with MACV GPc, we identified a single amino acid difference at position 122 between the strains Chicava and Carvallo GPc that significantly influenced the neutralization activity of the rabbit antisera. These findings indicate that polyclonal antibodies targeting the MACV glycoproteins can protect against lethal infection in a post-challenge setting. These data will help guide future antibody-based therapeutics development against NW arenaviruses.
PubMed: 38932403
DOI: 10.3390/vaccines12060674 -
Vaccines Jun 2024Currently, vaccination with influenza vaccines is still an effective strategy to prevent infection by seasonal influenza virus in spite of some drawbacks with them.... (Review)
Review
Currently, vaccination with influenza vaccines is still an effective strategy to prevent infection by seasonal influenza virus in spite of some drawbacks with them. However, due to the rapid evolution of influenza viruses, including seasonal influenza viruses and emerging zoonotic influenza viruses, there is an urgent need to develop broad-spectrum influenza vaccines to cope with the evolution of influenza viruses. Nucleic acid vaccines might meet the requirements well. Nucleic acid vaccines are classified into DNA vaccines and RNA vaccines. Both types induced potent cellular and humoral immune responses, showing great promise for the development of universal influenza vaccines. In this review, the current status of an influenza universal nucleic acid vaccine was summarized.
PubMed: 38932393
DOI: 10.3390/vaccines12060664 -
Vaccines Jun 2024Sublingual vaccines offer the benefits of inducing mucosal immunity to protect against respiratory viruses, including Severe Acute Respiratory Syndrome Coronavirus 2...
Sublingual vaccines offer the benefits of inducing mucosal immunity to protect against respiratory viruses, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and influenza, while also enabling needle-free self-administration. In a previous study, a sublingual SARS-CoV-2 vaccination was created by combining a recombinafigureCoV-2 spike protein receptor-binding domain antigen with a double strand RNA Poly(I:C) adjuvant. This vaccine was tested on nonhuman primates, Cynomolgus macaques. This study examined the immune and inflammatory responses elicited by the sublingual influenza vaccine containing hemagglutinin (HA) antigen and Poly(I:C) adjuvants, and assessed the safety of this vaccine in nonhuman primates. The Poly(I:C)-adjuvanted sublingual vaccine induced both mucosal and systemic immunities. Specifically, the sublingual vaccine produced HA-specific secretory IgA antibodies in saliva and nasal washings, and HA-specific IgA and IgG were detected in the blood. This vaccine appeared to be safe, as judged from the results of blood tests and plasma C-reactive protein levels. Notably, sublingual vaccination neither increased the production of inflammation-associated cytokines-IFN-alpha, IFN-gamma, and IL-17-in the blood, nor upregulated the gene expression of proinflammatory cytokines-IL12A, IL12B, IFNA1, IFNB1, CD69, and granzyme B-in white blood cells. Moreover, DNA microarray analyses revealed that sublingual vaccination evoked both enhancing and suppressing expression changes in genes associated with immune-related responses in cynomolgus monkeys. Therefore, the sublingual vaccine with the Poly(I:C) adjuvant is safe, and creates a balanced state of enhancing and suppressing the immune-related response.
PubMed: 38932372
DOI: 10.3390/vaccines12060643 -
Vaccines Jun 2024Inactivated and live attenuated vaccines are the mainstays of preventing viral poultry diseases. However, the development of recombinant DNA technology in recent years... (Review)
Review
Inactivated and live attenuated vaccines are the mainstays of preventing viral poultry diseases. However, the development of recombinant DNA technology in recent years has enabled the generation of recombinant virus vector vaccines, which have the advantages of preventing multiple diseases simultaneously and simplifying the vaccination schedule. More importantly, some can induce a protective immune response in the presence of maternal antibodies and offer long-term immune protection. These advantages compensate for the shortcomings of traditional vaccines. This review describes the construction and characterization of primarily poultry vaccine vectors, including fowl poxvirus (FPV), fowl adenovirus (FAdV), Newcastle disease virus (NDV), Marek's disease virus (MDV), and herpesvirus of turkey (HVT). In addition, the pathogens targeted and the immunoprotective effect of different poultry recombinant virus vector vaccines are also presented. Finally, this review discusses the challenges in developing vector vaccines and proposes strategies for improving immune efficacy.
PubMed: 38932359
DOI: 10.3390/vaccines12060630