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Journal of Virology Oct 2023The hepatitis C virus is associated with nearly 300,000 deaths annually. At the core of the virus is an RNA-protein complex called the nucleocapsid, which consists of...
The hepatitis C virus is associated with nearly 300,000 deaths annually. At the core of the virus is an RNA-protein complex called the nucleocapsid, which consists of the viral genome and many copies of the core protein. Because the assembly of the nucleocapsid is a critical step in viral replication, a considerable amount of effort has been devoted to identifying antiviral therapeutics that can bind to the core protein and disrupt assembly. Although several candidates have been identified, little is known about how they interact with the core protein or how those interactions alter the structure and thus the function of this viral protein. Our work biochemically characterizes several of these binding interactions, highlighting both similarities and differences as well as strengths and weaknesses. These insights bolster the notion that this viral protein is a viable target for novel therapeutics and will help to guide future developments of these candidate antivirals.
Topics: Humans; Antiviral Agents; Hepacivirus; Hepatitis C; Nucleocapsid; Viral Core Proteins; Virus Assembly; Virus Replication; Single Molecule Imaging; Protein Binding
PubMed: 37772835
DOI: 10.1128/jvi.00892-23 -
Journal of the International AIDS... Dec 2023Unhealthy alcohol use significantly contributes to viral non-suppression among persons with HIV (PWH). It is unknown whether brief behavioural interventions to reduce... (Randomized Controlled Trial)
Randomized Controlled Trial
Effect of a brief alcohol counselling intervention on HIV viral suppression and alcohol use among persons with HIV and unhealthy alcohol use in Uganda and Kenya: a randomized controlled trial.
INTRODUCTION
Unhealthy alcohol use significantly contributes to viral non-suppression among persons with HIV (PWH). It is unknown whether brief behavioural interventions to reduce alcohol use can improve viral suppression among PWH with unhealthy alcohol use in sub-Saharan Africa (SSA).
METHODS
As part of the SEARCH study (NCT04810650), we conducted an individually randomized trial in Kenya and Uganda of a brief, skills-based alcohol intervention among PWH with self-reported unhealthy alcohol use (Alcohol Use Disorders Identification Test-Consumption [AUDIT-C], prior 3 months, ≥3/female; ≥4/male) and at risk of viral non-suppression, defined as either recent HIV viral non-suppression (≥400 copies/ml), missed visits, out of care or new diagnosis. The intervention included baseline and 3-month in-person counselling sessions with interim booster phone calls every 3 weeks. The primary outcome was HIV viral suppression (<400 copies/ml) at 24 weeks, and the secondary outcome was unhealthy alcohol use, defined by AUDIT-C or phosphatidylethanol (PEth), an alcohol biomarker, ≥50 ng/ml at 24 weeks.
RESULTS
Between April and September 2021, 401 persons (198 intervention, 203 control) were enrolled from HIV clinics in Uganda (58%) and Kenya (27%) and alcohol-serving venues in Kenya (15%). At baseline, 60% were virally suppressed. Viral suppression did not differ between arms at 24 weeks: suppression was 83% in intervention and 82% in control arms (RR: 1.01, 95% CI: 0.93-1.1). Among PWH with baseline viral non-suppression, 24-week suppression was 73% in intervention and 64% in control arms (RR 1.15, 95% CI: 0.93-1.43). Unhealthy alcohol use declined from 98% at baseline to 73% in intervention and 84% in control arms at 24 weeks (RR: 0.86, 95% CI: 0.79-0.94). Effects on unhealthy alcohol use were stronger among women (RR 0.70, 95% CI: 0.56-0.88) than men (RR 0.93, 95% CI: 0.85-1.01) and among participants with a baseline PEth⩽200 ng/ml (RR 0.68, 95% CI: 0.53-0.87) versus >200 ng/ml (RR 0.97, 95% CI: 0.92-1.02).
CONCLUSIONS
In a randomized trial of 401 PWH with unhealthy alcohol use and risk for viral non-suppression, a brief alcohol intervention reduced unhealthy alcohol use but did not affect viral suppression at 24 weeks. Brief alcohol interventions have the potential to improve the health of PWH in SSA by reducing alcohol use, a significant driver of HIV-associated co-morbidities.
Topics: Humans; Male; Female; HIV Infections; Alcoholism; Uganda; Kenya; Counseling; Ethanol
PubMed: 38054564
DOI: 10.1002/jia2.26187 -
Journal of Virology Oct 2023The biogenesis and clinical application of serum HBV pgRNA have been a research hotspot in recent years. This study further characterized the heterogeneity of the 3'...
The biogenesis and clinical application of serum HBV pgRNA have been a research hotspot in recent years. This study further characterized the heterogeneity of the 3' terminus of capsid RNA by utilizing a variety of experimental systems conditionally supporting HBV genome replication and secretion, and reveal that the 3' truncation of capsid pgRNA is catalyzed by cellular ribonuclease(s) and viral RNaseH at positions after and before 3' DR1, respectively, indicating the 3' DR1 as a boundary between the encapsidated portion of pgRNA for reverse transcription and the 3' unprotected terminus, which is independent of pgRNA length and the 3' terminal sequence. Thus, our study provides new insights into the mechanism of pgRNA encapsidation and reverse transcription, as well as the optimization of serum HBV RNA diagnostics.
Topics: Capsid; Genome, Viral; Hepatitis B; Hepatitis B virus; Reverse Transcription; Ribonuclease H; RNA, Viral; Virus Replication
PubMed: 37754759
DOI: 10.1128/jvi.00760-23 -
Viruses May 2024During viral infection, the innate immune system utilizes a variety of specific intracellular sensors to detect virus-derived nucleic acids and activate a series of... (Review)
Review
During viral infection, the innate immune system utilizes a variety of specific intracellular sensors to detect virus-derived nucleic acids and activate a series of cellular signaling cascades that produce type I IFNs and proinflammatory cytokines and chemokines. Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic double-stranded DNA virus that has been associated with a variety of human malignancies, including Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman disease. Infection with KSHV activates various DNA sensors, including cGAS, STING, IFI16, and DExD/H-box helicases. Activation of these DNA sensors induces the innate immune response to antagonize the virus. To counteract this, KSHV has developed countless strategies to evade or inhibit DNA sensing and facilitate its own infection. This review summarizes the major DNA-triggered sensing signaling pathways and details the current knowledge of DNA-sensing mechanisms involved in KSHV infection, as well as how KSHV evades antiviral signaling pathways to successfully establish latent infection and undergo lytic reactivation.
Topics: Herpesvirus 8, Human; Humans; Signal Transduction; Immunity, Innate; DNA, Viral; Herpesviridae Infections; Sarcoma, Kaposi; Nucleotidyltransferases; Host-Pathogen Interactions; Animals; Membrane Proteins; Nuclear Proteins; Phosphoproteins
PubMed: 38793630
DOI: 10.3390/v16050749 -
Journal of Clinical Medicine Apr 2024Cidofovir, an antiviral drug approved for cytomegalovirus retinitis, has emerged as an alternative treatment option for virally induced cutaneous and mucocutaneous... (Review)
Review
Cidofovir, an antiviral drug approved for cytomegalovirus retinitis, has emerged as an alternative treatment option for virally induced cutaneous and mucocutaneous conditions, as well as being trialed as a treatment for select neoplasms. In this review, we highlight the existing evidence, clinical uses, and rationale of using cidofovir for the treatment of cutaneous pathologies. A PubMed database literature search was conducted to identify relevant articles for inclusion in this review. Cidofovir has several cutaneous applications in various formulations including intravenous, topical, and subcutaneous administrations. Primarily through case reports, case series, and retrospective reviews, cidofovir has demonstrated efficacy in treating a variety of virally induced conditions-verruca vulgaris, herpes simplex virus, molluscum contagiosum-as well as in adjuvant treatment for select neoplasms. The drug has shown efficacy in immunocompromised and immunocompetent adults and children alike. The body of literature supports the use of cidofovir as an effective and well-tolerated treatment for many viral cutaneous pathologies, and encourages further study for its use as an adjuvant therapy for neoplastic disease.
PubMed: 38730991
DOI: 10.3390/jcm13092462 -
Journal of Virology Jul 2023During viral infection, host defensive proteins either enhance the host immune response or antagonize viral components directly. In this study, we report on the...
During viral infection, host defensive proteins either enhance the host immune response or antagonize viral components directly. In this study, we report on the following two mechanisms employed by zebrafish mitogen-activated protein kinase kinase 7 (MAP2K7) to protect the host during spring viremia of carp virus (SVCV) infection: stabilization of host IRF7 and degradation of SVCV P protein. , ( is a lethal mutation) zebrafish showed a higher lethality, more pronounced tissue damage, and more viral proteins in major immune organs than the controls. At the cellular level, overexpression of significantly enhanced host cell antiviral capacity, and viral replication and proliferation were significantly suppressed. Additionally, MAP2K7 interacted with the C terminus of IRF7 and stabilized IRF7 by increasing K63-linked polyubiquitination. On the other hand, during MAP2K7 overexpression, SVCV P proteins were significantly decreased. Further analysis demonstrated that SVCV P protein was degraded by the ubiquitin-proteasome pathway, as the attenuation of K63-linked polyubiquitination was mediated by MAP2K7. Furthermore, the deubiquitinase USP7 was indispensable in P protein degradation. These results confirm the dual functions of MAP2K7 during viral infection. Normally, during viral infection, host antiviral factors individually modulate the host immune response or antagonize viral components to defense infection. In the present study, we report that zebrafish MAP2K7 plays a crucial positive role in the host antiviral process. According to the weaker antiviral capacity of map2k7 zebrafish than that of the control, we find that MAP2K7 reduces host lethality through two pathways, as follows: enhancing K63-linked polyubiquitination to promote host IRF7 stability and attenuating K63-mediated polyubiquitination to degrade the SVCV P protein. These two mechanisms of MAP2K7 reveal a special antiviral response in lower vertebrates.
Topics: Animals; Fish Diseases; Interferon Regulatory Factors; Rhabdoviridae; Rhabdoviridae Infections; Ubiquitination; Zebrafish; Zebrafish Proteins; Protein Stability; Proteolysis; Viral Structural Proteins; Mitogen-Activated Protein Kinases; Up-Regulation
PubMed: 37367226
DOI: 10.1128/jvi.00532-23 -
PLoS Pathogens Oct 2023Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic double-stranded DNA virus and the etiologic agent of Kaposi's sarcoma and hyperinflammatory...
Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic double-stranded DNA virus and the etiologic agent of Kaposi's sarcoma and hyperinflammatory lymphoproliferative disorders. Understanding the mechanism by which KSHV increases the infected cell population is crucial for curing KSHV-associated diseases. Using scRNA-seq, we demonstrate that KSHV preferentially infects CD14+ monocytes, sustains viral lytic replication through the viral interleukin-6 (vIL-6), which activates STAT1 and 3, and induces an inflammatory gene expression program. To study the role of vIL-6 in monocytes upon KSHV infection, we generated recombinant KSHV with premature stop codon (vIL-6(-)) and its revertant viruses (vIL-6(+)). Infection of the recombinant viruses shows that both vIL-6(+) and vIL-6(-) KSHV infection induced indistinguishable host anti-viral response with STAT1 and 3 activations in monocytes; however, vIL-6(+), but not vIL-6(-), KSHV infection promoted the proliferation and differentiation of KSHV-infected monocytes into macrophages. The macrophages derived from vIL-6(+) KSHV infection showed a distinct transcriptional profile of elevated IFN-pathway activation with immune suppression and were compromised in T-cell stimulation function compared to those from vIL-6(-) KSHV infection or uninfected control. Notably, a viral nuclear long noncoding RNA (PAN RNA), which is required for sustaining KSHV gene expression, was substantially reduced in infected primary monocytes upon vIL-6(-) KSHV infection. These results highlight the critical role of vIL-6 in sustaining KSHV transcription in primary monocytes. Our findings also imply a clever strategy in which KSHV utilizes vIL-6 to secure its viral pool by expanding infected monocytes via differentiating into longer-lived dysfunctional macrophages. This mechanism may facilitate KSHV to escape from host immune surveillance and to support a lifelong infection.
Topics: Humans; Herpesvirus 8, Human; Interleukin-6; Monocytes; Sarcoma, Kaposi; Herpesviridae Infections; Macrophages; Immunologic Factors; Virus Replication
PubMed: 37883374
DOI: 10.1371/journal.ppat.1011703 -
Nucleic Acids Research Dec 2023Epstein-Barr virus (EBV) establishes lifelong asymptomatic infection by replication of its chromatinized episomes with the host genome. EBV exhibits different...
Epstein-Barr virus (EBV) establishes lifelong asymptomatic infection by replication of its chromatinized episomes with the host genome. EBV exhibits different latency-associated transcriptional repertoires, each with distinct three-dimensional structures. CTCF, Cohesin and PARP1 are involved in maintaining viral latency and establishing episome architecture. Epstein-Barr virus-associated gastric cancer (EBVaGC) represents 1.3-30.9% of all gastric cancers globally. EBV-positive gastric cancers exhibit an intermediate viral transcription profile known as 'Latency II', expressing specific viral genes and noncoding RNAs. In this study, we investigated the impact of PARP1 inhibition on CTCF/Cohesin binding in Type II latency. We observed destabilization of the binding of both factors, leading to a disrupted three-dimensional architecture of the episomes and an altered viral gene expression. Despite sharing the same CTCF binding profile, Type I, II and III latencies exhibit different 3D structures that correlate with variations in viral gene expression. Additionally, our analysis of H3K27ac-enriched interactions revealed differences between Type II latency episomes and a link to cellular transformation through docking of the EBV genome at specific sites of the Human genome, thus promoting oncogene expression. Overall, this work provides insights into the role of PARP1 in maintaining active latency and novel mechanisms of EBV-induced cellular transformation.
Topics: Humans; Epstein-Barr Virus Infections; Gene Expression; Genome, Viral; Herpesvirus 4, Human; Stomach Neoplasms; Virus Latency; Gene Expression Regulation, Viral
PubMed: 37889078
DOI: 10.1093/nar/gkad936 -
Current Opinion in Virology Jun 2024Influenza A virus (IAV) infections pose a global health challenge that necessitates a comprehensive understanding of the host immune response to devise effective... (Review)
Review
Influenza A virus (IAV) infections pose a global health challenge that necessitates a comprehensive understanding of the host immune response to devise effective therapeutic interventions. As monocytes and macrophages play crucial roles in host defence, inflammation, and repair, this review explores the intricate journey of these cells during and after IAV infection. First, we highlight the dynamics and functions of lung-resident macrophage populations post-IAV. Second, we review the current knowledge of recruited monocytes and monocyte-derived cells, emphasising their roles in viral clearance, inflammation, immunomodulation, and tissue repair. Third, we shed light on the consequences of IAV-induced macrophage alterations on long-term lung immunity. We conclude by underscoring current knowledge gaps and exciting prospects for future research in unravelling the complexities of macrophage responses to respiratory viral infections.
Topics: Humans; Monocytes; Influenza, Human; Influenza A virus; Macrophages; Animals; Lung; Orthomyxoviridae Infections; Inflammation
PubMed: 38564993
DOI: 10.1016/j.coviro.2024.101409 -
Frontiers in Cellular and Infection... 2023This comprehensive review examines the interplay between environmental virology, public health, and sanitation in the unique context of Kenya. The review sheds light on... (Review)
Review
This comprehensive review examines the interplay between environmental virology, public health, and sanitation in the unique context of Kenya. The review sheds light on the specific viral threats faced by the country, including waterborne viruses, zoonotic infections, and emerging viral diseases, and their implications for public health. It explores the prevailing public health challenges in Kenya associated with environmental viromics, such as infectious viral diseases, and the rising burden of other infectious particles. The role of sanitation in mitigating viral infections is highlighted, emphasising the importance of clean water supply, proper waste management, and hygienic practises. The review also presents strategies for strengthening environmental virology research in Kenya, including enhancing laboratory capacities and leveraging technological advancements. Furthermore, the policy implications and recommendations derived from the review emphasise the need for multi-sectoral collaboration, evidence-based decision-making, and long-term investments in infrastructure and behaviour change interventions. Implementing these strategies can enhance the understanding of environmental virology, improve public health outcomes, and ensure sustainable sanitation practises in Kenya, ultimately contributing to the well-being of the population and sustainable development.
Topics: Humans; Sanitation; Public Health; Kenya; Water Supply; Virus Diseases
PubMed: 37942480
DOI: 10.3389/fcimb.2023.1256822