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Nature Nov 2023Post-acute infection syndromes may develop after acute viral disease. Infection with SARS-CoV-2 can result in the development of a post-acute infection syndrome known as...
Post-acute infection syndromes may develop after acute viral disease. Infection with SARS-CoV-2 can result in the development of a post-acute infection syndrome known as long COVID. Individuals with long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions. However, the biological processes that are associated with the development and persistence of these symptoms are unclear. Here 275 individuals with or without long COVID were enrolled in a cross-sectional study that included multidimensional immune phenotyping and unbiased machine learning methods to identify biological features associated with long COVID. Marked differences were noted in circulating myeloid and lymphocyte populations relative to the matched controls, as well as evidence of exaggerated humoral responses directed against SARS-CoV-2 among participants with long COVID. Furthermore, higher antibody responses directed against non-SARS-CoV-2 viral pathogens were observed among individuals with long COVID, particularly Epstein-Barr virus. Levels of soluble immune mediators and hormones varied among groups, with cortisol levels being lower among participants with long COVID. Integration of immune phenotyping data into unbiased machine learning models identified the key features that are most strongly associated with long COVID status. Collectively, these findings may help to guide future studies into the pathobiology of long COVID and help with developing relevant biomarkers.
Topics: Humans; Antibodies, Viral; Biomarkers; Cross-Sectional Studies; Herpesvirus 4, Human; Hydrocortisone; Immunophenotyping; Lymphocytes; Machine Learning; Myeloid Cells; Post-Acute COVID-19 Syndrome; SARS-CoV-2
PubMed: 37748514
DOI: 10.1038/s41586-023-06651-y -
Nature Immunology Oct 2023Natural killer (NK) cells are innate cytotoxic lymphocytes with adaptive immune features, including antigen specificity, clonal expansion and memory. As such, NK cells...
Natural killer (NK) cells are innate cytotoxic lymphocytes with adaptive immune features, including antigen specificity, clonal expansion and memory. As such, NK cells share many transcriptional and epigenetic programs with their adaptive CD8 T cell siblings. Various signals ranging from antigen, co-stimulation and proinflammatory cytokines are required for optimal NK cell responses in mice and humans during virus infection; however, the integration of these signals remains unclear. In this study, we identified that the transcription factor IRF4 integrates signals to coordinate the NK cell response during mouse cytomegalovirus infection. Loss of IRF4 was detrimental to the expansion and differentiation of virus-specific NK cells. This defect was partially attributed to the inability of IRF4-deficient NK cells to uptake nutrients required for survival and memory generation. Altogether, these data suggest that IRF4 is a signal integrator that acts as a secondary metabolic checkpoint to orchestrate the adaptive response of NK cells during viral infection.
Topics: Humans; Mice; Animals; Trained Immunity; Killer Cells, Natural; CD8-Positive T-Lymphocytes; Cytomegalovirus Infections; Virus Diseases; Immunologic Memory
PubMed: 37697097
DOI: 10.1038/s41590-023-01620-z -
Journal of Controlled Release :... Dec 2023Nucleic acid-based therapy has emerged as a promising therapeutic approach for treating various diseases, such as genetic disorders, cancers, and viral infections.... (Review)
Review
Nucleic acid-based therapy has emerged as a promising therapeutic approach for treating various diseases, such as genetic disorders, cancers, and viral infections. Diverse nucleic acid delivery systems have been reported, and some, including lipid nanoparticles, have exhibited clinical success. In parallel, bioengineered nucleic acid delivery nanocarriers have also gained significant attention due to their flexible functional design and excellent biocompatibility. In this review, we summarize recent advances in bioengineered nucleic acid delivery nanocarriers, focusing on exosomes, cell membrane-derived nanovesicles, protein nanocages, and virus-like particles. We highlight their unique features, advantages for nucleic acid delivery, and biomedical applications. Furthermore, we discuss the challenges that bioengineered nanocarriers face towards clinical translation and the possible avenues for their further development. This review ultimately underlines the potential of bioengineered nanotechnology for the advancement of nucleic acid therapy.
Topics: Nucleic Acids; Nanotechnology; Proteins; Drug Delivery Systems; Nanoparticles
PubMed: 37879440
DOI: 10.1016/j.jconrel.2023.10.034 -
Nature Medicine Dec 2023Non-suppressible HIV-1 viremia (NSV) is defined as persistent low-level viremia on antiretroviral therapy (ART) without evidence of ART non-adherence or significant drug...
Non-suppressible HIV-1 viremia (NSV) is defined as persistent low-level viremia on antiretroviral therapy (ART) without evidence of ART non-adherence or significant drug resistance. Unraveling the mechanisms behind NSV would broaden our understanding of HIV-1 persistence. Here we analyzed plasma virus sequences in eight ART-treated individuals with NSV (88% male) and show that they are composed of large clones without evidence of viral evolution over time in those with longitudinal samples. We defined proviruses that match plasma HIV-1 RNA sequences as 'producer proviruses', and those that did not as 'non-producer proviruses'. Non-suppressible viremia arose from expanded clones of producer proviruses that were significantly larger than the genome-intact proviral reservoir of ART-suppressed individuals. Integration sites of producer proviruses were enriched in proximity to the activating H3K36me3 epigenetic mark. CD4 T cells from participants with NSV demonstrated upregulation of anti-apoptotic genes and downregulation of pro-apoptotic and type I/II interferon-related pathways. Furthermore, participants with NSV showed significantly lower HIV-specific CD8 T cell responses compared with untreated viremic controllers with similar viral loads. We identified potential critical host and viral mediators of NSV that may represent targets to disrupt HIV-1 persistence.
Topics: Humans; Male; Female; HIV-1; Viremia; Proviruses; HIV Seropositivity; HIV Infections; CD4-Positive T-Lymphocytes; RNA, Viral; Viral Load
PubMed: 37957382
DOI: 10.1038/s41591-023-02611-1 -
Journal of Molecular Cell Biology Apr 2024Lenacapavir, targeting the human immunodeficiency virus type-1 (HIV-1) capsid, is the first-in-class antiretroviral drug recently approved for clinical use. The... (Review)
Review
Lenacapavir, targeting the human immunodeficiency virus type-1 (HIV-1) capsid, is the first-in-class antiretroviral drug recently approved for clinical use. The development of Lenacapavir is attributed to the remarkable progress in our understanding of the capsid protein made during the last few years. Considered little more than a component of the virus shell to be shed early during infection, the capsid has been found to be a key player in the HIV-1 life cycle by interacting with multiple host factors, entering the nucleus, and directing integration. Here, we describe the key advances that led to this 'capsid revolution'.
Topics: Humans; HIV-1; Capsid Proteins; Capsid; HIV Infections; Anti-HIV Agents
PubMed: 38037430
DOI: 10.1093/jmcb/mjad076 -
Gut Jun 2024Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), mostly characterised by HBV integrations, is prevalent worldwide. Previous HBV studies mainly focused on...
OBJECTIVE
Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), mostly characterised by HBV integrations, is prevalent worldwide. Previous HBV studies mainly focused on a few hotspot integrations. However, the oncogenic role of the other HBV integrations remains unclear. This study aimed to elucidate HBV integration-induced tumourigenesis further.
DESIGN
Here, we illuminated the genomic structures encompassing HBV integrations in 124 HCCs across ages using whole genome sequencing and Nanopore long reads. We classified a repertoire of integration patterns featured by complex genomic rearrangement. We also conducted a clustered regularly interspaced short palindromic repeat (CRISPR)-based gain-of-function genetic screen in mouse hepatocytes. We individually activated each candidate gene in the mouse model to uncover HBV integration-mediated oncogenic aberration that elicits tumourigenesis in mice.
RESULTS
These HBV-mediated rearrangements are significantly enriched in a bridge-fusion-bridge pattern and interchromosomal translocations, and frequently led to a wide range of aberrations including driver copy number variations in chr 4q, 5p (), 6q, 8p, 16q, 9p (), 17p () and 13q (), and particularly, ultra-early amplifications in chr8q. Integrated HBV frequently contains complex structures correlated with the translocation distance. Paired breakpoints within each integration event usually exhibit different microhomology, likely mediated by different DNA repair mechanisms. HBV-mediated rearrangements significantly correlated with young age, higher HBV DNA level and mutations but were less prevalent in the patients subjected to prior antiviral therapies. Finally, we recapitulated the and amplification in chr8q led by HBV integration using CRISPR/Cas9 editing and demonstrated their tumourigenic potentials.
CONCLUSION
HBV integrations extensively reshape genomic structures and promote hepatocarcinogenesis (graphical abstract), which may occur early in a patient's life.
Topics: Carcinoma, Hepatocellular; Liver Neoplasms; Hepatitis B virus; Humans; Virus Integration; Animals; Mice; Male; Middle Aged; Female; Adult; Whole Genome Sequencing; DNA Copy Number Variations; Aged
PubMed: 38395437
DOI: 10.1136/gutjnl-2023-330414 -
MBio Jan 2024HIV-1 capsid protein (CA)-independently or by recruiting host factors-mediates several key steps of virus replication in the cytoplasm and nucleus of the target cell.... (Review)
Review
HIV-1 capsid protein (CA)-independently or by recruiting host factors-mediates several key steps of virus replication in the cytoplasm and nucleus of the target cell. Research in the recent years have established that CA is multifunctional and genetically fragile of all the HIV-1 proteins. Accordingly, CA has emerged as a validated and high priority therapeutic target, and the first CA-targeting antiviral drug was recently approved for treating multi-drug resistant HIV-1 infection. However, development of next generation CA inhibitors depends on a better understanding of CA's known roles, as well as probing of CA's novel roles, in HIV-1 replication. In this timely review, we present an updated overview of the current state of our understanding of CA's multifunctional role in HIV-1 replication-with a special emphasis on CA's newfound post-nuclear roles, highlight the pressing knowledge gaps, and discuss directions for future research.
Topics: Humans; Capsid; Capsid Proteins; DNA, Viral; HIV-1; HIV Seropositivity; HIV Infections; Virus Replication; Virus Integration
PubMed: 38085100
DOI: 10.1128/mbio.00212-22 -
International Journal of Molecular... Dec 2023Intrahepatic cholangiocarcinoma (ICC) is a relatively uncommon but highly aggressive primary liver cancer that originates within the liver. The aim of this study is to... (Review)
Review
Intrahepatic cholangiocarcinoma (ICC) is a relatively uncommon but highly aggressive primary liver cancer that originates within the liver. The aim of this study is to review the molecular profile of intrahepatic cholangiocarcinoma and its implications for prognostication and decision-making. This comprehensive characterization of ICC tumors sheds light on the disease's underlying biology and offers a foundation for more personalized treatment strategies. This is a narrative review of the prognostic and therapeutic role of the molecular profile of ICC. Knowing the molecular profile of tumors helps determine prognosis and support certain target therapies. The molecular panel in ICC helps to select patients for specific therapies, predict treatment responses, and monitor treatment responses. Precision medicine in ICC can promote improvement in prognosis and reduce unnecessary toxicity and might have a significant role in the management of ICC in the following years. The main mutations in ICC are in (), (), (), and (). The rate of mutations varies significantly for each population. Targeting and is challenging due to the natural characteristics of these genes. Different stages of clinical studies have shown encouraging results with inhibitors of mutated and target therapy for downstream effectors. () fusions are an important target in patients with ICC. Immune checkpoint blockade can be applied to a small percentage of ICC patients. Molecular profiling in ICC represents a groundbreaking approach to understanding and managing this complex liver cancer. As our comprehension of ICC's molecular intricacies continues to expand, so does the potential for offering patients more precise and effective treatments. The integration of molecular profiling into clinical practice signifies the dawn of a new era in ICC care, emphasizing personalized medicine in the ongoing battle against this malignancy.
Topics: Humans; Proto-Oncogene Proteins p21(ras); Cholangiocarcinoma; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Liver Neoplasms
PubMed: 38203635
DOI: 10.3390/ijms25010461 -
Cell Feb 2024CD4 T cells with latent HIV-1 infection persist despite treatment with antiretroviral agents and represent the main barrier to a cure of HIV-1 infection.... (Randomized Controlled Trial)
Randomized Controlled Trial
CD4 T cells with latent HIV-1 infection persist despite treatment with antiretroviral agents and represent the main barrier to a cure of HIV-1 infection. Pharmacological disruption of viral latency may expose HIV-1-infected cells to host immune activity, but the clinical efficacy of latency-reversing agents for reducing HIV-1 persistence remains to be proven. Here, we show in a randomized-controlled human clinical trial that the histone deacetylase inhibitor panobinostat, when administered in combination with pegylated interferon-α2a, induces a structural transformation of the HIV-1 reservoir cell pool, characterized by a disproportionate overrepresentation of HIV-1 proviruses integrated in ZNF genes and in chromatin regions with reduced H3K27ac marks, the molecular target sites for panobinostat. By contrast, proviruses near H3K27ac marks were actively selected against, likely due to increased susceptibility to panobinostat. These data suggest that latency-reversing treatment can increase the immunological vulnerability of HIV-1 reservoir cells and accelerate the selection of epigenetically privileged HIV-1 proviruses.
Topics: Humans; HIV Infections; HIV-1; Panobinostat; Proviruses; Virus Latency; Histone Deacetylase Inhibitors; Interferon-alpha
PubMed: 38367616
DOI: 10.1016/j.cell.2024.01.037 -
AIDS Research and Therapy Sep 2023Human immunodeficiency virus type 1 (HIV-1) is the primary epidemic strain in China. Its genome contains two regulatory genes (tat and rev), three structural genes (gag,... (Review)
Review
Human immunodeficiency virus type 1 (HIV-1) is the primary epidemic strain in China. Its genome contains two regulatory genes (tat and rev), three structural genes (gag, pol, and env), and four accessory genes (nef, vpr, vpu, and vif). Long terminal repeats (LTRs) in thegenome regulate integration, duplication, and expression of viral gene. The permissibility of HIV-1 infection hinges on the host cell cycle status. HIV-1 replicates by exploiting various cellular processes via upregulation or downregulation of specific cellular proteins that also control viral pathogenesis. For example, HIV-1 regulates the life cycle of p53, which in turn contributes significantly to HIV-1 pathogenesis. In this article, we review the interaction between HIV-1-associated factors and p53, providing information on their regulatory and molecular mechanisms, hinting possible directions for further research.
Topics: Humans; HIV-1; Tumor Suppressor Protein p53; HIV Infections; China; Genes, Viral
PubMed: 37691100
DOI: 10.1186/s12981-023-00563-7