Antiviral Therapy Research Articles

Multicenter Analysis of Acute Retinal Necrosis: Clinical Characteristics, Viral Pathogens, and Diagnostic Predictive Factors

ABSTRACT Purpose This multicenter study aimed to investigate the clinical characteristics and factors associated with specific viral pathogens in patients with acute retinal necrosis (ARN). Methods A retrospective multicenter cohort study included ARN patients who underwent aqueous or vitreous polymerase chain reaction (PCR) testing. Multivariable mixed-effects Poisson regression was used to identify factors associated with viral pathogens. Results A total of 56 patients (65 eyes) with ARN were included, with a mean age was 39.9 ± 23.2 years. Anterior chamber cell showed significant inflammation in 89.2%, while vitreous haze was present in 100%. Multifocal retinitis was found in 92.3% of cases. Among these, 49.2% had diffuse or confluent patterns, 15.4% were circumferential, and 23.1% showed satellite lesions. Additionally, 18.5% were ameboid or scalloped shape, while 9.2% had wedge shapes. Varicella zoster virus (VZV) was the most common pathogen (30.8%), followed by Herpes simplex virus (HSV) (13.8%), Cytomegalovirus (CMV) (10.8%), Epstein-Barr virus (EBV) (9.2%), and human herpesvirus (HHV) (3.0%). Co-infections were observed in 20% of eyes. CMV-related ARN was significantly associated with wedge-shaped retinitis (aRR 4.19) and immunocompromised host (aRR 8.8). Younger age and optic disc edema (aRR 5.41) were correlated with HSV-related ARN. Conclusion VZV was the predominant viral pathogen, with the increasing prevalence of CMV, EBV, and co-infection. Wedge-shaped retinitis and immunocompromised status were notably associated with CMV-related ARN, findings that may guide antiviral therapy decisions in settings where PCR diagnostics are either unavailable or delayed, ultimately improving visual outcomes.

Development and characterization of a reverse genetics system for the lineage II Chicava strain of Machupo virus in a guinea pig model.

Machupo virus (MACV) is a New World mammarenavirus (hereafter referred to as "arenavirus") and the etiologic agent of Bolivian hemorrhagic fever (BHF). No vaccine or antiviral therapy exists for BHF, which causes up to 35% mortality in humans. New World arenaviruses evolve separately in different locations. To date, up to eight lineages of MACV have been identified in Bolivia. While the prototype MACV Carvallo strain belongs to lineage I discovered in the Memore Province in the 1960, the MACV lineage II strains have become the dominantly-circulating lineage in the same province since 1993. We report the development of a reverse genetics system for the MACV lineage II Chicava strain, using a pRF42 plasmid encoding the L and S segment genomic RNA under the transcriptional control of a murine DNA-dependent RNA polymerase I promoter sequence. Rescue of the recombinant MACV Chicava strain (rMACV-Chicava) was accomplished by expression of the L protein and nucleoprotein genes of the MACV Carvallo strain in trans in transfected baby hamster kidney (BHK-21) cells. We characterized the multiplication kinetics of rMACV-Chicava in African green monkey kidney epithelial Vero cells, followed by determining the virulence phenotype in outbred Hartley guinea pigs. We demonstrated that the multiplication kinetics in Vero cells, virulence phenotype in guinea pigs, and neutralizing antibody titers are indistinguishable between rMACV-Chicava and the wild-type parental virus. We conclude that rMACV-Chicava provides a useful model system to investigate the emergence of MACV lineage II strains and the guinea pig model has utility for the development of candidate vaccines and therapeutic antibodies for BHF.

Prevalence of chronic hepatitis B virus infection among children in Uzbekistan: Impact of vaccination.

Uzbekistan, a highly endemic country for hepatitis B virus (HBV), introduced infant vaccination with hepatitis B vaccine (HepB) in 2001. Since 2002, it had ≥90% reported immunization coverage for ≥3 doses of HepB (HepB3) and the birth dose (HepB-BD). However, the impact of HepB vaccination and the progress towards achieving the regional hepatitis B control and global viral hepatitis B elimination goals had not been assessed. To determine current HBsAg prevalence among children in Uzbekistan, in 2022, we conducted a nationwide serosurvey among schoolchildren (grades 1-3) using a stratified, multi-stage cluster design. Participants' basic demographics and HepB immunization information were obtained. Blood specimens were tested for HBsAg using a WHO-prequalified rapid test (Bioline HBsAg WB, Abbott Diagnostics). Samples with positive and indeterminate results were tested for HBsAg by ELISA (Murex HBsAg Version3, Diasorine). Weighted proportions and adjusted 95% confidence intervals (CI) were calculated. Of 4119 children enrolled in 148 schools, blood was collected from 3753 (91.1%) and immunization data were available for 3833 (93.3%). National HBsAg prevalence was 0.20% (adjusted 95% CI, 0.09%-0.38%). Among children with available immunization data, 97.7% (97.2%-98.1%) received ≥3 HepB doses and 94.9% (94.1%-95.5%) received HepB-BD, including timely HepB-BD in 93.7% (92.9%-94.5%). The survey demonstrated that Uzbekistan has met the <0.5% European regional HBsAg seroprevalence target and has made substantial progress towards meeting the <0.1% HBsAg seroprevalence target for the elimination of HBV mother to-child transmission (MTCT). Based on these findings and≥90% HepB-BD and HepB3 coverage, in 2023, Uzbekistan was validated as having achieved the regional hepatitis B control goal. To achieve the elimination of MTCT of HBV, additional interventions, including improving antenatal screening for HBsAg, providing antiviral treatment of eligible HBsAg-positive pregnant women and hepatitis B immunoglobulin to infants born to HBsAg-positive mothers, should be considered.

Phytochemical-based nanosystems: recent advances and emerging application in antiviral photodynamic therapy.

Phytochemicals are typically natural bioactive compounds or metabolites produced by plants. Phytochemical-loaded nanocarrier systems, designed to overcome bioavailability limitations and enhance therapeutic effects, have garnered significant attention in recent years. The coronavirus disease 2019 (COVID-19) pandemic has intensified interest in the therapeutic application of phytochemicals to combat viral infections. This review explores nanoparticle-based treatment strategies incorporating phytochemicals for antiviral application, highlighting their demonstrated antiviral mechanisms. It specifically examines the antiviral activities of phytochemical-loaded nanosystems against (i) influenza virus (IAV), respiratory syncytial virus (RSV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); (ii) mosquito-borne viruses [dengue (DENV), Zika (ZIKV), and Chikungunya (CHIKV)]; and (iii) sexually transmitted/blood borne viruses [e.g. herpes simplex virus (HSV), human papillomavirus (HPV), and human immunodeficiency virus (HIV)]. Furthermore, this review highlights the emerging role of these nanosystems in photodynamic therapy (PDT)-mediated attenuation of viral proliferation, and offers a perspective on the future directions of research in this promising area of multimodal therapeutic approach.

Evaluation and Management of Congenital Cytomegalovirus Infection.

The purpose of this review is to serve as an update on congenital cytomegalovirus (CMV) evaluation and management for obstetrician-gynecologists and to provide a framework for counseling birthing people at risk for or diagnosed with a primary CMV infection or reactivation or reinfection during pregnancy. A DNA virus, CMV is the most common congenital viral infection and the most common cause of nongenetic childhood hearing loss in the United States. The risk of congenital CMV infection from transplacental viral transfer depends on the gestational age at the time of maternal infection and whether the infection is primary or nonprimary. Although the risk of congenital CMV infection is lower with infection at earlier gestational ages, clinical sequelae are more severe with maternal infections earlier in gestation. At present, routine screening for maternal CMV infection is not recommended by U.S. guidelines. When maternal primary infection is confirmed in early pregnancy, emerging data support consideration of maternal antiviral therapy to prevent congenital CMV infection. When congenital CMV infection is confirmed, typically after an abnormal prenatal ultrasound result, there are more limited data on the utility of maternal antiviral therapy. Universal newborn screening for congenital CMV infection is not mandatory in most U.S. states at present. Newborns diagnosed with congenital CMV infection undergo an extensive evaluation to determine whether neurologic symptoms are present, which guides postnatal evaluation and management. In this review, we discuss the diagnosis and management of maternal CMV infection, the risk and diagnosis of congenital CMV infection, prevention and potential treatment of congenital CMV infection in utero, and neonatal congenital CMV infection diagnosis and management.

Community prevalence of blood-borne viruses (hepatitis B and HIV) in Ireland.

Chronic infection with hepatitis B virus and HIV causes significant morbidity and mortality. Effective antiviral treatment is available for both. Ireland has historically been considered a low prevalence country. However, with increasing inward migration and diversity, this may be changing. The aim of this study was to measure the community prevalence of hepatitis B virus and HIV infections in Irish residents born between the years 1965 and 1985. Anonymised residual serum samples from blood tests ordered by community general practitioners and tested in eight general hospital laboratories, spread across Ireland, were analysed for the presence of Hepatitis B surface antigen and antibodies to HIV. A total of 6080 samples were analysed for hepatitis B surface antigen including 2993 males, 2807 females and 280 samples for which gender was not recorded. HBsAg was detected in 28/6067 samples giving an estimated prevalence of 0.46% (95% CI 0.32-0.67%). Antibodies to HIV were identified in 18/6064 giving an estimated prevalence of 0.33% (95% CI 0.19-0.47%). The prevalence of both hepatitis B and HIV was significantly higher in Cork (Southwest Ireland) than other centres: hepatitis B (12/1050 vs 16/5017, p = 0.014) and HIV (11/1049 vs 7/5015, p < 0.001). The prevalence of hepatitis B virus and HIV infections in this cohort appear to be higher than previously estimated. In addition, their prevalence in the Cork area appears particularly high. Whether this represents a true prevalence or a chance finding will require confirmatory studies.

The endoplasmic reticulum degradation-enhancing α-mannosidase-like protein 3 attenuates the unfolded protein response and has pro-survival and pro-viral roles in hepatoma cells and hepatocellular carcinoma patients

BackgroundChronic hepatitis B virus (HBV) infection is a major risk for development of hepatocellular carcinoma (HCC), a frequent malignancy with a poor survival rate. HBV infection results in significant endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) signaling, a contributing factor to carcinogenesis. As part of the UPR, the ER-associated degradation (ERAD) pathway is responsible for removing the burden of misfolded secretory proteins, to re-establish cellular homeostasis. Emerging evidence indicates consistent upregulation of ERAD factors, including members of the ER degradation-enhancing alpha-mannosidase-like protein (EDEM) family in infection and various tumor types. However, the significance of this gene expression pattern in HBV-driven pathology is just beginning to be deciphered.MethodsIn this study we quantified the expression of the ERAD factor EDEM3, in a cohort of HCC patients with and without HBV infection, and validated our results by analysis of publically available transcriptomic and microarray data sets. We performed mechanistic studies in HepaRG cells with modulated EDEM3 expression to address UPR, ERAD, autophagy and apoptosis signaling, and their consequences on HBV infection.ResultsOur work revealed significantly elevated EDEM3 expression in HCC tissues irrespective of HBV infection, while the highest levels were observed in tissues from HBV-infected patients. Investigation of published transcriptomic data sets confirmed EDEM3 upregulation in independent HCC patient cohorts, associated with tumor progression, poor survival prognosis and resistance to therapy. EDEM3-overexpressing hepatic cells exhibited attenuated UPR and activated secretory autophagy, which promoted HBV production. Conversely, cell depletion of EDEM3 resulted in significant ER stress inducing pro-apoptotic mechanisms and cell death.ConclusionsWe provide evidence of major implications of the ERAD pathway in HBV infection and HCC development and progression. Our results suggest that ERAD activation in HBV-infected cells is a protective mechanism against prolonged ER stress, potentially contributing to establishment of chronic HBV infection and promoting tumorigenesis. Developing specific inhibitors for ERAD factors may be an attractive approach to improve efficiency of current antiviral and anticancer therapies.

A novel neutralizing antibody recognizing a conserved conformational epitope in PDCoV S1 protein and its therapeutic efficacy in piglets.

Porcine deltacoronavirus (PDCoV) is a novel swine enteropathogenic coronavirus that poses a potential threat to public health. Developing effective antiviral therapies is crucial for its prevention and control. Here, we demonstrated that mAb 4A6 shows promise as a treatment against PDCoV. Antibody therapy experiments conducted on PDCoV-infected piglets revealed that administering mAb 4A6 once or twice could delay the onset of diarrhea symptoms, reduce the severity of diarrhea, and decrease virus shedding. Furthermore, we characterized the conformational epitope (S461, P462, T463, E465, and Y467) recognized by mAb 4A6 through an integrated approach involving phage display peptide library, molecular docking, and alanine scanning mutagenesis. More importantly, mAb 4A6 exhibits a broad-spectrum neutralizing activity against different PDCoV strains. These findings indicate that mAb 4A6 has promising therapeutic value for PDCoV-infected piglets, and the identification of mAb 4A6 recognized epitope may provide a new idea for the identification of conformational epitopes.

Long-term serum ferritin dynamics in patients receiving antiviral treatment for hepatitis C virus infection.

Limited data exists regarding the long-term serum ferritin dynamics following sustained virologic response (SVR12) and factors associated with trends in changes among patients undergoing treatment for hepatitis C virus (HCV). Serum ferritin levels were assessed biannually in 1538 participants undergoing direct-acting antivirals (DAAs) or peginterferon plus ribavirin (PR) with a median of follow-up of 5.0 years after off-treatment week 12. We compared the differences in time-dependent slope coefficients of serum ferritin levels for factors of interest using the generalized estimating equations to identify predictors associated with favorable serum ferritin evolution. Using univariable analysis, SVR12, aged ≤50 year, absence of metabolic dysfunction-associated steatotic liver disease (MASLD), and pre-treatment HCV RNA level ≤2,000,000 IU/mL were associated with favorable ferritin evolution. Multivariable analysis showed that SVR12 (adjusted slope coefficient difference: 7.50ng/mL/year [95% CI: 3.37 to -11.63], p<0.001) and absence of MASLD (adjusted slope coefficient difference: 4.16ng/mL/year [95% CI: 7.91 to -0.41], p=0.022) predicted favorable ferritin evolution. Among participants achieving SVR12, the ferritin evolution was not affected by DAA or PR treatment (crude slope coefficient difference: 3.33ng/mL/year [95% CI: 12.78 to 6.12], p=0.49). Absence of MASLD was associated with favorable ferritin evolution (adjusted slope coefficient difference: 2.86ng/mL/year [95% CI: 5.39 to -0.33], p=0.021). Patients achieving SVR12, irrespective of types of treatment, exhibited more favorable long-term ferritin dynamics compared to those not achieving SVR12. Absence of MASLD may help improve long-term ferritin dynamics among patients achieving SVR12.

A Review of Potentials of Carica Papaya Leaves in Dengue Viral Infection - Insights of Clinical and Preclinical Studies.

One of the most widespread arboviral diseases in the world, dengue virus disease (DVD) is primarily found in tropical and subtropical regions, affecting 129 countries. The main way that the dengue virus (DENV) spreads is through the bite of a female Aedes aegypti mosquito. Symptomatic therapy and supportive care are the primary methods of managing patients with DENV infection as there is currently no approved antiviral medication for this condition. Since the guidelines from the AYUSH Ministry, Government of India, recommend 10 ml of carica papaya leaf extract (CPLE) twice daily for seven days, to treat dengue fever clinically, we plan to review the potential of carica papaya in managing DENV infection.Using terms like dengue, dengue fever, dengue hemorrhagic fever, dengue shock syndrome, and carica papaya, the literature was searched in databases like Medline/PubMed Central/PubMed, Google Scholar, Science Direct, EBSCO, Scopus, Web of Science, EMBASE, Directory of open access journals (DOAJ), and reference lists to find articles relevant to the clinical, in-vivo, in-vitro, and in-silico studies evaluating the efficacy of carica papaya in the management of dengue viral infection. This review included English-language publications that supported the use of carica papaya in the treatment of dengue fever, but it excluded publications that were duplicates.Numerous preclinical and clinical investigations, such as in-vitro, in-vivo, and in-silico studies, have identified carica papaya's anti-dengue potential. The pleiotropic effects of carica papaya, including its anti-thrombocytopenic activity, immunomodulatory effects, and larvicidal property against the Aedes aegypti mosquito species, have also been confirmed by numerous in-vitro and in-vivo studies. These effects can help patients with dengue fever by elevating their platelet count and alleviating other symptoms.To hasten recovery and reduce hospital stays, patients with DENV infection may take carica papaya leaf extract (CPLE) in addition to supportive care and symptomatic treatment. Additional randomized controlled clinical trials would be necessary to confirm the safety and effectiveness of CPLE in patients with DENV infection.

The role of M2 proteins of pneumoviruses in transcription regulation, prevention of hypermutation, and activation of the type I interferon pathway.

Human metapneumovirus (HMPV) is an important causative agent of respiratory tract disease. Fundamental knowledge of the interaction between HMPV and the innate immune system could lead to the design of novel antiviral therapies. Previously, we demonstrated that HMPV M2-2 deletion mutants had hypermutated genomes and contained defective interfering particles (DIs), which are potent inducers of the IFN response. Here, we investigated the role of the HMPV M2-2 protein as IFN antagonist using chimeric HMPV expressing M2 proteins of other pneumoviruses: respiratory syncytial virus (RSV) and avian metapneumovirus type C (AMPV/C). Chimeric HMPVs expressing the M2 proteins of RSV or AMPV/C were attenuated in HEp-2 cells but did not activate the IFN response, and their genomes were not hypermutated. In contrast, chimeric HMPVs expressing the M2-2 proteins of RSV and AMPV/C, in combination with HMPV M2-1, did activate the IFN response, and their genomes were hypermutated. Investigation of the role of the pneumovirus M2 proteins in transcription regulation demonstrated that the M2-2 protein, only in concerted action with autologous M2-1 protein, acted as a transcription elongation factor. As a second approach, chimeric RSV in which the IFN antagonists NS1 and NS2 were replaced by the HMPV M2-2 gene failed to suppress an IFN response, indicating that the HMPV M2-2 protein is not a potent IFN antagonist. These data indicate that expression of autologous M2-1 and M2-2 proteins is important for the fidelity of the RNA-dependent RNA polymerase, necessary to prevent the accumulation of mutations, and possibly DIs, thereby preventing activation of the IFN responses.IMPORTANCEThe M2-2 protein of human metapneumovirus is suggested to function as a type I interferon antagonist, a function so far not assigned to the M2 proteins of other pneumoviruses. Although M2-2 deletion mutants of HMPV activate the type I interferon pathway, these mutants have hypermutated genomes and contain defective interfering RNAs, known to activate the interferon pathway. Here, we show that the M2-2 protein, in concerted action with autologous M2-1 protein, acts as a transcription elongation factor, which could explain the accumulation of DIs in M2-2 deletion mutants. Additionally, chimeric RSV in which the IFN antagonists NS1 and NS2 were replaced by the HMPV M2-2 gene failed to suppress an IFN response. These data indicate that expression of autologous M2-1 and M2-2 proteins is required for the fidelity of the RNA-dependent RNA polymerase to prevent genome hypermutation and activation of the type I IFN pathway.

The impact of remdesivir on SARS-CoV-2 evolution in vivo.

The impact of remdesivir on SARS-CoV-2 diversity and evolution in vivo has remained unclear. In this single-center, retrospective cohort study, we assessed SARS-CoV-2 diversification and diversity over time in a cohort of hospitalized patients who did or did not receive remdesivir. Whole genome sequencing was performed on 98 paired specimens collected from 49 patients before and after remdesivir administration. Genetic divergence between paired specimens was not significantly different from what was observed in paired specimens from patients who did not receive the drug. However, when comparing minority variants, several positions showed preferential diversification after remdesivir treatment, several of which were associated with different variants of concern. Most notably, remdesivir administration resulted in strong selection for a nonsynonymous mutation in nsp12, G671S, previously associated with enhanced viral fitness. This same mutation was found enriched in a second cohort of 143 inpatients with specimens collected after remdesivir administration compared to controls. Only one other mutation previously implicated in remdesivir resistance (nsp12:V792I) was found to be preferentially selected for after remdesivir administration. These data suggest that SARS-CoV-2 variants with enhanced replicative fitness may be selected for in the presence of antiviral therapy as an indirect means to overcome this selective pressure.

Pseudorabies virus infection triggers pUL46-mediated phosphorylation of connexin-43 and closure of gap junctions to promote intercellular virus spread.

Gap junctions (GJs) play a pivotal role in intercellular communication between eukaryotic cells, including transfer of biomolecules that contribute to the innate and adaptive immune response. However, if and how viruses affect gap junction intercellular communication (GJIC) remains largely unexplored. Here, we describe how the alphaherpesvirus pseudorabies virus (PRV) triggers ERK1/2-mediated phosphorylation of the main gap junction component connexin 43 (Cx43) and closure of GJIC, which depends on the viral protein pUL46. Consequently, a UL46null PRV mutant is unable to phosphorylate Cx43 or inhibit GJIC and displays reduced intercellular spread, which is effectively rescued by pharmacological inhibition of GJIC. Intercellular spread of UL46null PRV is also rescued by inhibition of the stimulator of interferon genes (STING), suggesting that pUL46-mediated suppression of GJIC contributes to intercellular virus spread by hindering intercellular communication that activates STING. The current study identifies key viral and cellular proteins involved in alphaherpesvirus-mediated suppression of GJIC and reveals that GJIC inhibition enhances virus intercellular spread, thereby opening new avenues for the design of targeted antiviral therapies.

“If that would have lessened my symptoms, that would have been great...”: a qualitative study about the acceptability of tecovirimat as treatment for mpox

BackgroundTecovirimat, an antiviral treatment for smallpox, was approved as a treatment for mpox by the European Medicines Agency in January 2022. Approval was granted under “exceptional circumstances” based on effectiveness found in pre-clinical challenge studies in animals and safety studies in humans showing minimal side effects. As clinical efficacy studies are still ongoing, there is currently limited information with regard to the acceptability of tecovirimat to treat mpox. The aim of this study is to understand prospective acceptability of use of tecovirimat as treatment for mpox.MethodsA co-produced, qualitative, focus group study design was conducted with a theoretically informed sample of people from communities at higher risk and with experience of mpox illness. Thirteen participants took part: all self-identified as cisgender male, 1 self-identified as Black British, 1 as British Asian, 5 as White, 3 as White British, 3 as White Other. Inclusion criteria were as follows: experience of mpox illness; age 18 and over; living in the United Kingdom (UK); living in the UK during 2022 mpox outbreak. Focus groups were recorded, transcribed and thematically analysed using a combination inductive and deductive coding informed by the Treatment Acceptability Framework.ResultsVery few participants were aware of tecovirimat as a treatment option and none were offered it during their mpox illness. Key factors influencing acceptability found in this study were as follows: levels of trust in medicine; level of information; provider communication approach; quality of experience of mpox care. Marginalised communities at highest risk of mpox may have prior experience of structural discrimination which can greatly influence treatment acceptability.ConclusionsThis exploratory study suggest that offering tecovirimat (or comparable emergency-licensed treatments) to people with mpox is acceptable, although uptake will depend on knowledge of mpox treatment options, trust in medicine and medical professionals and provision of relevant information and choice. To increase acceptability of such treatments, clinicians should ensure patients are aware of mpox symptom management options, including pain relief; acknowledge and address patient concerns upfront and within the context of non-stigmatising care; and communicate offers in a consistent and supportive manner in line with locally approved eligibility criteria and protocols at the time.

C-X-C chemokine receptor type 5+CD8+ T cells as immune regulators in hepatitis Be antigen-positive chronic hepatitis B under interferon-alpha treatment

BACKGROUND C-X-C chemokine receptor type 5 (CXCR5)+CD8+ T cells represent a unique immune subset with dual roles, functioning as cytotoxic cells in persistent viral infections while promoting B cell responses. Despite their importance, the specific role of CXCR5+CD8+ T cells in chronic hepatitis B (CHB), particularly during interferon-alpha (IFN-α) treatment, is not fully understood. This study aims to elucidate the relationship between CXCR5+CD8+ T cells and sustained serologic response (SR) in patients undergoing 48 weeks of pegylated IFN-α (peg-IFN-α) treatment for CHB. AIM To elucidate the relationship between CXCR5+CD8+ T cells and sustained SR in patients undergoing 48 weeks of peg-IFN-α treatment for CHB. METHODS This study enrolled 60 patients with hepatitis Be antigen (HBeAg)-positive CHB undergoing 48 weeks of peg-IFN-α treatment. Participants were assessed for eligibility based on criteria such as persistent HBsAg-positive status for at least six months, HBeAb-negative, hepatitis B virus DNA levels exceeding 2 × 104 copies/mL, and alanine aminotransferase (ALT) levels between 2 and 10 times the upper limit of normal. Blood samples were collected at baseline and at weeks 12, 24, 48, and a 24-week treatment-free follow-up (week 72) to measure serum interleukin (IL)-21 concentration via ELISA and to analyze CXCR5 and programmed death-ligand 1 (PD-L1) expression on CD8+ T cells by flow cytometry, CXCR5 is a chemokine receptor that directs immune cells to specific tissues, while PD-L1 is a protein that regulates immune responses by inhibiting T cell activity. RESULTS Patients with CHB exhibited significantly lower levels of circulating CXCR5+CD8+ T cells compared to healthy controls (P &lt; 0.01). Notably, CXCR5+CD8+ T cells were prominently expressed in patients who achieved sustained SR compared to non-SR (NSR). A significant correlation was observed between CXCR5 and PD-L1 expression (r = -0.189, P = 0.002). However, there was no significant correlation between serum IL-21 levels and CXCR5+CD8+ lymphocytes (r = -0.03, P = 0.625) or serum ALT levels (r = 0.026, P = 0.678). CONCLUSION The enhanced expression of CXCR5+CD8+ T cells in patients achieving HBeAg seroconversion during IFN-α treatment suggests that these cells play a crucial role in antiviral immune responses against hepatitis B. This study highlights the potential of CXCR5+CD8+ T cells as immune regulators in CHB, which may inform future therapeutic strategies to optimize antiviral treatments.

Potential therapeutics and vaccines: Current progress and challenges in developing antiviral treatments or vaccines for Oropouche virus.

Oropouche virus (OROV), an emerging arbovirus, poses a significant public health challenge in tropical and subtropical regions, with no licensed vaccines or antiviral therapies currently available. This review explores recent advancements in therapeutic strategies and vaccine development for OROV, focusing on molecular mechanisms of viral replication, identification of potential antiviral targets, and the role of immunotherapy in managing infections. Promising antiviral candidates, including ribavirin, mycophenolic acid, and interferon, have demonstrated efficacy in in vitro studies, offering a foundation for further investigation. The challenges of preclinical and clinical development, such as high mutation rates, immune response variability, and vaccine delivery hurdles, are critically analyzed. By addressing the progress and remaining gaps, this article aims to provide a comprehensive overview to inform future research and facilitate the development of effective antiviral strategies and vaccines for OROV.

Friend or Foe? Safety and Efficacy of Hepatitis B Viremic Solid Organ Allograft into Seronegative Recipients.

Long-term outcomes of HBV nucleic acid test (NAT)-positive (+) allograft use in seronegative liver transplant (LT) and kidney transplant (KT) recipients remains unknown despite being incorporated into practice by select centers. This study compares long-term outcomes between HBV NAT+ and NAT-negative (-) allografts in seronegative recipients. All recipients of an HBV core antibody-positive (HBcAb+) LT or KT were prospectively evaluated at a single transplant center from 6/2015-3/2023 and compared by NAT status. Study endpoints were post-transplant viremia, patient, and graft survival. 144 HBcAb+ LT and 220 HBcAb+ KT were performed including 57 (39.6%) NAT+ LT's and 123 (55.9%) NAT+ KT's with a median follow-up of 36 months. 14.8% of NAT+ and 3.5% of NAT- LTs experienced post-transplant viremia (p=0.004). At the time of last follow-up, 100% of NAT+ and 98.9% of NAT- LT recipients had undetectable HBV DNA (p=0.31). 4.1% of NAT+ and 6.2% of NAT- KTs experienced post-transplant viremia (p=0.12). At the time of last follow-up, 100% of NAT+ and 96.9% of NAT- KT recipients had undetectable HBV DNA (p=0.85). LT and KT patient and graft survival were not different between groups (p>0.05). With close surveillance, HBV seronegative recipients transplanted with NAT+ allografts can develop viremia which can be cleared with antiviral therapy. This is the first and largest single-center study reporting longer-term experience with HBV NAT+ allografts in seronegative recipients demonstrating the safe expansion of the donor pool.

Harnessing antiviral RNAi therapeutics for pandemic viruses: SARS-CoV-2 and HIV.

Using the knowledge from decades of research into RNA-based therapies, the COVID-19 pandemic response saw the rapid design, testing and production of the first ever mRNA vaccines approved for human use in the clinic. This breakthrough has been a significant milestone for RNA therapeutics and vaccines, driving an exponential growth of research into the field. The development of novel RNA therapeutics targeting high-threat pathogens, that pose a substantial risk to global health, could transform the future of health delivery. In this review, we provide a detailed overview of the two RNA interference (RNAi) pathways and how antiviral RNAi therapies can be used to treat acute or chronic diseases caused by the pandemic viruses SARS-CoV-2 and HIV, respectively. We also provide insights into short-interfering RNA (siRNA) delivery systems, with a focus on how lipid nanoparticles can be functionalized to achieve targeted delivery to specific sites of disease. This review will provide the current developments of SARS-CoV-2 and HIV targeted siRNAs, highlighting strategies to advance the progression of antiviral siRNA along the clinical development pathway.

Antiviral treatment of chronic hepatitis D virus infection: To combine or not to combine?

Antiviral treatment of chronic hepatitis D virus infection: To combine or not to combine?

Sialidase fusion protein protects against influenza infection in a cigarette smoke-induced model of COPD.

First- and secondhand smokers are at an increased risk for influenza virus (IFV)-related respiratory failure and death. Despite approved influenza antiviral treatments, there is an unmet need for treatments that can improve outcomes in populations at risk for respiratory failure, including tobacco users with Chronic Obstructive Pulmonary Disease (COPD). Here we show that the sialidase fusion protein, DAS181, reduced viral burden, mitigated inflammation, and attenuated lung function loss, consistent with broad-spectrum anti-influenza responses in a mouse model of COPD and IFV-A infection. Treatment with DAS181 reprogramed the sialic acid-binding immunoglobulin-like lectins (Siglecs) in alveolar macrophages, increased expression of phagocytic marker CD169, and downregulated inhibitory Siglec-F and Siglec-H molecules. Upon reinfection, mice treated with DAS181 showed activated and protective memory response in the lungs. Collectively, we show that this sialidase fusion protein promotes a beneficial immunomodulatory reaction in the lungs, supporting a new IFV-A therapeutic option for at-risk smokers.