Search Results (262)

Sulforaphane (SFN), a natural compound found in cruciferous vegetables, mobilizes the transcription factor NRF2 to protect macrophages from HIV-1. SFN/NRF2 exerts this protective effect by promoting the reduced phosphorylation of the antiviral protein SAMHD1. Phosphorylation at threonine 592 (T592) potently inhibits the capacity of SAMHD1 to restrict HIV-1. How SFN, and other NRF2 mobilizers reduce SAMHD1 T592 phosphorylation is unclear. p21 (CDKN1A) is an NRF2-responsive protein that accumulates in primary macrophages after SFN treatment. p21 blocks SAMHD1 T592 phosphorylation through the inhibition of several cyclin-dependent kinases. We therefore hypothesized that SFN acts through p21 to reduce SAMHD1 T592 phosphorylation in macrophages. Here, we use RNAi, CRISPR-Cas9, and pharmacological inhibition to deplete or delete p21 in macrophages and demonstrate that p21 is necessary for SFN to efficiently reduce SAMHD1 T592 phosphorylation and restrict HIV-1 transduction. Full article

In May 2025, a new and welcome Pandemic Treaty was signed. The success of this treaty for the management of future pandemics depends on a re-evaluation of the importance of previous well-established treaty-based international human rights norms in controlling health crises. During the COVID-19 pandemic, public health responses globally were characterised by poor preparation, uncertainty, and hasty and sometimes perverse decisions. International human rights norms, especially health rights, and other treaty obligations were honoured more in their breach than their observance. The lessons learned from public health strategies that had integrated international human rights norms into the control and management of the HIV/AIDS pandemic were either ignored or forgotten. Early public health attempts to control the HIV/AIDs pandemic were hobbled by data breaches, travel restrictions, compulsory reporting, stigma, and misinformation about how the virus spread. This was replaced by a more successful human rights-based approach (HRBA) that used health rights indicators to identify groups susceptible to the disease but difficult to reach with conventional public health policies. The efficacy of health rights indicators and HRB methodology to remove barriers to treatment and suppress pandemics should have been seriously considered in strategies to control COVID-19. The article claims that failure to do this meant that more lives were lost than necessary and more people were left with serious long-term health effects. This article explores the practical significance of the international human rights legal framework, especially health rights, as trialled during the HIV/AIDS pandemic, for the management of COVID-19 and other pandemics. Full article

The 2022–2024 mpox outbreak in Europe was dominated by MPXV Clade IIb and generally mild, but recent Clade I/Ib detections and early local transmission have changed preparedness needs. We performed a PRISMA-ScR scoping review of European mpox evidence from 2022 to 2026, supplemented by global and African data where regional evidence was sparse, covering clades, host determinants of severe disease, and antiviral efficacy and resistance, and ranking the evidence gaps. European Clade IIb surveillance showed very low mortality (10 deaths among 22,662 cases; case fatality 0.04%), contrasting with 3–11% estimates for Clade I/Ib in affected African settings, although comparisons are confounded by age, health-system access and comorbidity. Severe European disease was driven mainly by immune compromise: non-HIV immunosuppression, uncontrolled HIV and CD4 counts < 200 cells/µL were the most consistent markers, while women were a small minority of cases, with higher hospitalisation risk, especially in pregnancy. Tecovirimat failed to improve outcomes in four randomised trials, F13L-associated resistance was reported in advanced HIV, and its European mpox use was subsequently restricted. The evidence base is strongest for mild Clade IIb infection in immunocompetent adults and weakest for the groups most likely to need treatment. Preparedness should prioritise harmonised genomic surveillance, severity-stratified cohort data and adaptive therapeutic trials enrolling immunocompromised, paediatric, pregnant and older patients. Full article

Theories on the early steps of the HIV-1 life cycle have been radically revised over the past five years. The long-held assumption that the capsid fully disassembles in the cytoplasm has given way to a more nuanced view: Cytoplasmic disassembly does occur and, in several myeloid systems, is increasingly linked to cytosolic cDNA sensing and to abortive infection. However, a substantial fraction of intact or nearly intact capsid cores instead traverse the nuclear pore complex (NPC) and, upon interacting with the host factor CPSF6, induce liquid–liquid phase separation. This leads to the formation of biomolecular condensates, termed HIV-1 membraneless organelles (HIV-1-MLOs), which subsequently merge with nuclear speckles (NSs). In this Perspective we read these condensates along five interlocking axes. First, the virus drives the host phase separation of cleavage and polyadenylation specificity factor 6 (CPSF6), which quickly fuses with another MLO: the NS composed of the speckle scaffold factors, SON and SRRM2. Second, the resulting condensate behaves as a catalytic site that concentrates the reverse-transcription machinery and thereby promotes integration of the viral DNA into speckle-associated chromatin (SPADs). Third, the same compartment is the final layer of a stratified programme of innate immune evasion, shielding nascent double-stranded DNA from cGAS–STING after cytoplasmic restriction factors and sensors have been outmanoeuvred. Fourth, although demonstrated only in vitro, stable HIV-1-MLOs can maintain the viral RNA genome in the presence of a reverse-transcription inhibitor. Upon removal of the inhibitor, reverse transcription resumes, mirroring, to some extent, the situation in individuals undergoing interruption of antiretroviral therapy and suggesting that these structures may act as a pre-integration reservoir. Fifth, and still largely unexplored, the sanctuary has a pharmacological dimension: anatomical lymphoid compartments, and possibly the condensate itself through selective small-molecule partitioning, may limit antiretroviral drug access. We situate HIV-1-MLOs within the convergent condensate strategies of SARS-CoV-2 and other viruses, and we discuss the clinical, diagnostic, therapeutic, and vaccine implications, including capsid inhibitors as “block-and-expose” tools. Full article

Background: Lymphoepithelial sialadenitis (LESA) is a chronic lymphoid-rich inflammatory disorder of the salivary glands that is strongly associated with Sjögren’s disease and may overlap clinically, radiologically, and histopathologically with IgG4-related sialadenitis, HIV-associated lymphoepithelial lesions, chronic sialadenitis, salivary gland tumors, and extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). Objective: This scoping review mapped current evidence on diagnostic challenges, differential diagnostic criteria, management strategies, and surveillance considerations for LESA. Eligibility criteria: Sources were selected using the Population–Concept–Context framework and included the literature addressing salivary gland lymphoepithelial lesions, LESA, Sjögren’s disease-associated salivary gland involvement, or related lymphoid-rich salivary gland disorders published from 2010 onward. Sources of evidence and charting methods: Google Scholar was searched, records were screened in sequential stages, and relevant data were charted narratively across clinical, serological, imaging, histopathological, immunophenotypic, molecular, therapeutic, and follow-up domains. Results: Thirty-seven sources were included. The evidence indicates that LESA is usually characterized by chronic lymphoplasmacytic inflammation, acinar atrophy, lymphoepithelial lesions, and preserved lobular architecture; however, these findings may overlap with early or established MALT lymphoma. Immunohistochemistry, assessment of light-chain restriction, clonality testing, serological markers, and imaging are useful adjuncts, but no single test is independently definitive. Conservative management and symptomatic care are appropriate for stable disease, whereas corticosteroids, immunomodulatory therapy, sialendoscopy, surgery, radiotherapy, or systemic lymphoma therapy may be considered according to clinical context. Conclusions: LESA requires integrated clinicopathological interpretation and multidisciplinary follow-up. Key evidence gaps include the absence of standardized LESA-specific diagnostic criteria, limited validation of molecular and flow cytometric approaches in salivary gland specimens, and lack of consensus surveillance protocols. Full article

Background: Tuberculosis (TB) remains a leading cause of global morbidity and mortality, yet its impact extends far beyond microbiological cure. Many TB survivors experience persistent structural lung damage or functional impairment consistent with post-TB lung disease, while growing evidence highlights long-term non-respiratory health outcomes. Synthesizing evidence across lung and non- respiratory health outcomes, along with their risk factors, is critical to inform long-term TB care. Methods: We conducted a scoping review including systematic reviews reporting on post-TB long-term health outcomes. A search was performed in PubMed/MEDLINE on 27 July 2025, using terms related to “tuberculosis,” “systematic review,” “meta-analysis,” “sequelae” and “long-term health outcomes,” without language restrictions. Results: Nine systematic reviews met inclusion criteria. Most focused on pulmonary outcomes and consistently demonstrated that TB is associated with chronic airflow obstruction, reduced lung function, and an increased long-term risk of lung cancer, although residual confounding from environmental, clinical, and socioeconomic factors cannot be excluded. While younger adults are more prone to developing COPD after TB in high TB burden settings, older individuals face a higher risk of broader post-TB lung sequelae. Evidence suggested that TB survivors are at increased risk of non-respiratory complications. HIV co-infection, low CD4 counts, older age, pre-existing hepatitis, prior TB treatment, and hypoalbuminemia were associated with post-TB liver injury, while baseline hearing impairment and HIV co-infection increased the likelihood of post-TB hearing loss. TB was also linked to elevated risk of several non-pulmonary cancers, including oesophageal, cervical, hematological, pancreatic, and gastric malignancies, with the highest risk within the first year after TB diagnosis and persisting, though attenuated, in subsequent years. Conclusion: TB should be viewed as a chronic condition with enduring lung and non-respiratory health outcomes. TB survivors face increased risks of COPD, lung cancer, and a range of non-respiratory health outcomes, including hepatic and auditory complications, particularly among high-risk groups, such as those living with HIV infection, along with baseline hearing and hepatic impairment. Public health programmes must extend care beyond microbiological cure to include integrated, post-TB long-term monitoring of lung, hepatic and hearing across all ages, including malignancy surveillance, after baseline assessments to identify high-risk TB survivors. Future research should also elucidate risk factors for post-TB malignancy, and clarify the relationship between neurological, renal, and musculoskeletal sequelae and TB to inform evidence-based TB survivorship care. Full article

Background: Congenital infections included in the TORCH complex remain an important cause of fetal and neonatal morbidity and mortality, being associated with miscarriage, intrauterine growth restriction, congenital malformations, neurological impairment, and long-term developmental sequelae. Prenatal serological screening may contribute to the early identification of maternal infections and facilitate preventive and therapeutic interventions. However, data regarding the utilization of TORCH screening and associated socio-demographic determinants in Romania remain limited. Objective: This study aimed to evaluate the self-reported uptake of prenatal serological testing for one or more infections included in the TORCH complex, particularly Toxoplasma gondii, rubella virus, cytomegalovirus (CMV), herpes simplex virus (HSV), and syphilis, and to identify socio-demographic, obstetrical, and prenatal care-related factors associated with TORCH testing among pregnant women in Romania. Materials and Methods: A cross-sectional observational study was conducted using an online self-administered questionnaire completed by 1301 pregnant women from Romania. Data collection was performed between August 2022 and March 2023 through digital platforms, including social media and pregnancy-related forums. The primary outcome was self-reported performance of serological testing for at least one TORCH-related infection during pregnancy. Associations between explanatory variables and TORCH testing were evaluated using chi-square tests and multivariable binary logistic regression models. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Results: Overall, 75.6% of participants reported undergoing serological testing for at least one infection included in the TORCH complex during pregnancy, while 49.3% reported a complete TORCH panel. The most frequently reported investigations were for Toxoplasma gondii (92.8%) and rubella virus (89.9%), whereas HSV testing was less commonly reported (42.5%). Lower educational level was the strongest independent factor associated with reduced likelihood of TORCH testing (adjusted OR = 0.08; 95% CI: 0.03–0.19; p < 0.001) (adjusted OR—aOR). Unemployment status (aOR = 0.70; 95% CI: 0.50–0.99; p = 0.045) and multiparity (aOR = 0.62; 95% CI: 0.49–0.77; p < 0.001) were also associated with lower testing uptake. In contrast, participation in prenatal education programs was associated with increased likelihood of TORCH testing (aOR = 1.37; 95% CI: 1.04–1.80; p = 0.024). The number of prenatal consultations was not independently associated with testing uptake. Conclusions: The uptake of prenatal serological screening for congenital infections (assessed using an expanded Romanian panel that includes hepatitis B and HIV in addition to the classical TORCH agents) in Romania appears to be influenced predominantly by socio-educational and behavioral factors rather than by the quantitative utilization of prenatal care services alone. Given the online recruitment strategy and the predominantly urban and highly educated sample, the reported uptake rates may overestimate population-level coverage. Significant inequalities in access to preventive prenatal investigations were observed, particularly among women with lower educational and socio-economic status. Strengthening prenatal education programs and improving equitable access to standardized prenatal screening may contribute to optimizing congenital infection prevention and maternal–fetal health outcomes. Full article

Background/Objectives: To compare the efficacy and safety of a single dose versus three weekly doses of benzathine penicillin G (BPG) for the treatment of early syphilis. Methods: We searched Embase, PubMed, and Scopus for randomized controlled trials (RCTs) and prospective comparative studies published in English up to September 2025. The primary outcome was serological cure (≥4-fold decline in non-treponemal titers) at 6–12 months, analyzed on an intention-to-treat (ITT) basis. Risk of bias was assessed using RoB 2 for RCTs and ROBINS-I for non-randomized studies; certainty of evidence was rated with GRADE. Data were synthesized using random-effects meta-analysis and trial sequential analysis (TSA). Results: Three studies (n = 886) met the inclusion criteria. The primary ITT meta-analysis showed no significant difference in serological cure between the three-dose and single-dose regimens (risk ratio [RR] 1.06; 95% CI 0.92–1.21; p = 0.42), with substantial heterogeneity. In an exploratory pre-specified subgroup of patients with high baseline RPR (≥1:32), the three-dose regimen was associated with higher cure rates (RR 1.12; 95% CI 1.02–1.23; p = 0.02; I² = 0%), but no significant benefit was seen for people with HIV (PWH) (RR 1.08; p = 0.13) or for those with CD4 counts <350 cells/mm³. Risk of bias was serious across all studies, and GRADE certainty was very low for efficacy and low for safety. In a post hoc per-protocol analysis restricted to early latent syphilis, the three-dose regimen yielded higher serological cure (pooled risk difference 12%, 95% CI 1–23; p = 0.03). TSA indicated that the evidence is inconclusive and underpowered. Conclusions: On the basis of the ITT analysis, a single dose of BPG appears to remain effective and safe for most cases of early syphilis, including in PWH, supporting current CDC and WHO recommendations. The apparent advantages of three doses in high-titer and early latent subgroups derive from exploratory and post hoc analyses of studies at high risk of bias with very low certainty of evidence and should be regarded as hypothesis-generating rather than practice-changing. Adequately powered, well-designed trials are needed before any dose stratification can be recommended. Full article

Human immunodeficiency virus type 1 exhibits extensive genetic diversity, which has important implications for molecular epidemiology, recombinant-pattern assessment, and antiretroviral resistance surveillance. In Mexico, HIV-1 molecular surveillance has historically relied mainly on partial pol gene sequencing, limiting the ability to compare lineage assignments across gag, pol, and env regions. We analyzed plasma samples from 40 treatment-naïve adults receiving care at a tertiary-care hospital in Mexico using a commercial amplicon-based multiregion HIV-1 genomic sequencing workflow. DeepChek^® was used as the primary workflow for read processing, mutation calling, region-level subtype assignment, and antiretroviral resistance interpretation. Resistance interpretation was restricted to antiretroviral target regions with sufficient coverage, mainly reverse transcriptase, protease, integrase, and capsid, when available. Drug resistance mutations were identified in 6/40 participants (15.0%) when mutation-level resistance findings in RT, PR, and IN were considered; one additional sample showed a capsid inhibitor-nonsusceptible NGS call. NNRTI-associated findings were identified in 2/40 patients (5.0%), whereas NRTI- and PI-associated findings were identified in 1/40 patients (2.5%). Accessory or secondary INSTI-associated substitutions were detected in 2/40 patients (5.0%). Region-level subtype analysis revealed frequent discordant assignments across amplified segments, which is consistent with complex mosaic profiles; however, these findings are interpreted as region-level subtypes and recombinant-pattern assignments rather than continuous whole-genome recombination maps. One sample had insufficient RT/PROT/INT coverage for drug resistance interpretation in the complete DeepChek report and was retained only for regions meeting quality thresholds. These findings support the value of multiregion HIV-1 sequencing for local molecular surveillance while emphasizing the need for transparent region-level coverage reporting, cautious interpretation of recombinant-pattern calls, and transparent repository reporting. Full article

Background/Objectives: Rifampicin-resistant tuberculosis (RR-TB) and HIV co-infection remain major contributors to morbidity and mortality, particularly in high-burden settings. HIV-related clinical factors, including viral suppression, CD4-defined immune status, HIV drug resistance, virological failure, and ART failure, may influence RR-TB treatment response; however, existing evidence remains fragmented. This systematic review and meta-analysis protocol aims to synthesize evidence on the impact of HIV viral suppression, immune status, and HIV drug resistance/ART resistance status on RR-TB treatment outcomes. Methods: This protocol was developed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines. Published peer-reviewed studies and relevant grey literature from January 2005 to December 2025 will be searched in PubMed/MEDLINE, Cochrane Library, Embase, Web of Science, ScienceDirect, EBSCOhost, PsycINFO, Google Scholar, and other relevant sources. No language restriction will be applied at the search stage. Where feasible, non-English records will be translated for title/abstract and full-text screening. Two reviewers will independently screen studies, extract data, and assess study quality, with disagreements resolved by a third reviewer. Study-level risk of bias will be assessed using design-appropriate tools, and the certainty of evidence for each outcome will be evaluated using GRADE. Results: Evidence will be synthesized narratively and, where studies are sufficiently homogeneous, quantitatively through meta-analysis. Outcomes of interest will include treatment success, treatment failure, mortality, treatment completion, microbiological cure, and adverse events. Subgroup analyses will be considered by viral suppression status, CD4-defined immune status, HIV drug resistance/ART resistance status, geographic region, and treatment regimen where data permit. Conclusions: This review will provide evidence on how HIV viral suppression, immune status, and HIV drug resistance/ART resistance influence RR-TB treatment outcomes. The findings may inform integrated TB/HIV care, clinical monitoring, and treatment strategies for individuals co-infected with HIV and RR-TB. Full article

Protease inhibitors (PIs) remain important components of HIV-2 treatment, but resistance genotyping is frequently challenging in individuals with low or undetectable plasma viremia. Proviral DNA sequencing may provide access to archived viral variants and improve understanding of long-term resistance and clinical evolution. In this retrospective longitudinal study, 27 individuals with HIV-2, both ART-experienced and ART-naïve, followed at a hospital in Lisbon, were analyzed. The HIV-2 protease gene was amplified from peripheral blood mononuclear cell-derived proviral DNA, cloned, and sequenced (Sanger sequencing) at baseline and, for ART-treated participants, after eight years of follow-up. Resistance profiles were interpreted using the Stanford HIVdb, HIV-2EU, and Rega algorithms. Clinical data, including ART history, CD4 counts, and plasma viral load, were collected longitudinally. Amino acid diversity was assessed using Shannon entropy, and longitudinal CD4 dynamics were evaluated using mixed-effects models with time-varying ART exposure. Sensitivity analyses were performed using generalized estimating equations (GEE). A total of 222 clonal HIV-2 protease sequences clustered within group A. Major PI resistance mutations were detected in 21.4% of ART-experienced and 23.1% of ART-naïve individuals at baseline. Longitudinal resistance trajectories varied across participants, including persistence, apparent emergence, and non-detection of previously identified mutations. Mixed-effects modeling revealed substantial inter-individual variability in CD4 trajectories, with no statistically significant associations observed between CD4 evolution and ART status, time, or their interaction. GEE analyses yielded consistent results, supporting robustness across modeling frameworks. Entropy analysis identified localized sequence diversity changes restricted to a small number of protease residues, with positions 60 and 75 differing between groups at baseline and position 21 showing longitudinal variation among treated participants. This study demonstrates that proviral DNA sequencing captures archived HIV-2 protease diversity and reveals persistent and dynamic resistance patterns within the viral reservoir. While no population-level association between ART exposure and CD4 trajectory was observed, marked inter-individual variability highlights the complexity of longitudinal immune recovery in HIV-2 infection. These findings support the value of proviral sequencing as a complementary research tool for characterizing long-term viral evolution in settings where plasma-based genotyping is limited. Full article

Combined antiretroviral therapy (cART) has transformed HIV into a manageable chronic disease. However, people living with HIV (PLWH) experience a 16-year reduction in comorbidity-free life expectancy compared to HIV-negative individuals, driven by persistent chronic immune activation despite virological suppression. Serious non-AIDS events (SNAEs)—including cardiovascular disease, metabolic disorders, and malignancies—now represent the predominant cause of morbidity. This narrative review provides a clinician-oriented synthesis of immunopathophysiological mechanisms driving chronic inflammation in treated HIV infection, focusing on the gut–immune axis, restriction factors, trained immunity, biomarker-guided risk stratification, and therapeutic strategies. We searched PubMed/MEDLINE, Embase, and Web of Science through April 2026 using terms related to HIV chronic immune activation, gut-associated lymphoid tissue, microbial translocation, inflammaging, restriction factors, trained immunity, and biomarkers. This review followed the SANRA checklist. Irreversible destruction of gut-associated lymphoid tissue (GALT), intestinal barrier dysfunction, microbial translocation, maladaptive trained immunity, persistent myeloid activation with NLRP3 inflammasome signaling and cellular senescence, and viral reservoir persistence collectively perpetuate systemic inflammation. Biomarkers, including sCD14, IL-6, and suPAR, independently predict mortality but are not pathogen-specific. The REPRIEVE trial demonstrated a 36% reduction in cardiovascular risk with pitavastatin (HR 0.64, 95% CI 0.48–0.84), validating inflammation as a therapeutic target. Integration of early cART, statin therapy, optimal antiretroviral selection, and emerging strategies—including GLP-1 receptor agonists and gut-directed therapies—offers a practical framework for reducing inflammation-associated comorbidities in virologically suppressed PLWH. Full article

Despite prolonged viral inhibition with combination antiretroviral therapy (ART), HIV-1 survives as genetically intact, replication-capable proviruses within durable CD4+ T-cell fractions, involving central memory, transitional memory, and stem cell-like memory populations, as well as within tissue-resident compartments including lymphoid follicles and gut-associated lymphoid tissue. Reservoir stability is preserved via clonal growth of infected cells and epigenetic processes that impose proviral transcriptional silencing. As a result, current therapeutic approaches seek to either directly alter proviral survival or to improve immune-driven elimination of infected cells. At the molecular level, investigational strategies such as CRISPR–Cas9 and CRISPR–Cas12 gene-editing systems are intended to remove or induce inactivating mutations inside embedded proviral DNA, as well as alter host entrance co-receptors such as CCR5 to provide cellular resistance to infection. In addition, pharmacologic latency regulation is being studied via histone deacetylase inhibitors, protein kinase C agonists, and bromodomain inhibitors to reverse latency, along with Tat inhibitors and other transcriptional repressors aimed to persistently silence proviral expression. Moreover, immunological techniques aim to counteract inefficient endogenous antiviral defenses. Broadly neutralizing antibodies with tailored Fc-driven effector functions are under examination for both neutralization and antibody-dependent cellular cytotoxicity. Therapeutic vaccine approaches seek to elevate polyfunctional HIV-specific CD8+ T-cell responses, while adoptive cellular approaches, involving CAR-T cells aiming HIV envelope epitopes, remain in early clinical research. Immune checkpoint blockade is also being investigated to reverse T-cell depletion inside reservoir-rich tissues. Nevertheless, the key obstacles continue to be the diverse reservoir composition, restricted tissue penetration, viral escape, and safety limitations. The molecular and translational obstacles that characterize attempts toward an HIV cure must be addressed through ongoing multidisciplinary research. Full article

Natural bioactive polysaccharides have been investigated for their ability to modulate antiviral immune responses. Polysaccharide peptide (PSP) from Coriolus versicolor previously restricted human immunodeficiency virus type 1 (HIV-1) entry into monocytic cells through a protein kinase R (PKR)-dependent cytoskeletal mechanism. However, its impact on antiviral signaling in adaptive cluster of differentiation 4 (CD4)+ T-cell models remains incompletely defined. Here, we evaluated concentration- and time-dependent effects of PSP (50–1000 µg/mL) in Jurkat T cells over 3 and 6 days. Cell viability was assessed by MTT, trypan blue exclusion, and viable cell density analysis. Immunoblotting and reverse transcription quantitative polymerase chain reaction (RT-qPCR) were performed to examine Toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), signal transducer and activator of transcription 1 and 2 (STAT1/STAT2), PKR, interferon gamma (IFN-γ), and cofilin-1 signaling. PSP did not induce cytotoxicity at any concentration. Instead, PSP promoted dose- and time-dependent upregulation of intracellular TLR4, PKR, phospho-PKR (Thr446), Cofilin-1, phospho-Cofilin-1 (Ser3), phospho-STAT1 (Tyr701), phospho-STAT2 (Tyr690), phospho-NF-κB (Ser536), and IFN-γ, with amplified responses at Day 6. These changes were paralleled by transcriptional induction of antiviral-associated genes. Collectively, PSP induces coordinated interferon (IFN)-associated and cytoskeletal regulatory signaling in Jurkat T cells without cytotoxicity, providing a mechanistic framework for future evaluation of viral permissiveness and antiviral responses in adaptive immune models. Full article

Background: Hepatitis B virus (HBV) infection continues to be a major public health concern, especially in sub-Saharan Africa, where widespread epidemics and restricted availability of long-term antiviral therapies result in higher mortality and morbidity rates. Drug repurposing represents a strategic approach to accelerate the discovery of effective therapies by leveraging agents with demonstrated antiviral and immunomodulatory activity. Product Nkabinde (PN) is a patented African polyherbal formulation initially developed for the treatment of HIV. Recent experimental studies demonstrate PN’s potent anti-HIV activity and significant immunomodulatory effects in human immune cells, implicating host-directed mechanisms relevant to chronic viral infections. This study combines an integrative application of network pharmacology and molecular docking to evaluate the repurposing potential of PN as a multi-target agent in HBV. Method: Bioactive components of PN were screened, and compound-associated targets were intersected with HBV-associated genes (proteins) to construct a protein–protein interaction (PPI) network. Topological analysis identified 10 hub targets (STAT1, STAT3, SRC, HCK, EGFR, SYK, PIK3CA, PIK3CB, PIK3R1, and PTPN11). Gene Ontology and KEGG pathway enrichment were performed with an FDR cut-off < 0.05. Significantly enriched pathways included JAK–STAT signaling, chemokine signaling, EGFR-TKI resistance, PI3K complex signaling, and viral infection pathways, particularly those related to Kaposi sarcoma virus and HSV-1, indicating immunoregulatory and antiviral roles. Molecular docking was performed using AutoDock Vina 1.1.2 to evaluate binding affinity and interaction mode of key PN phytochemicals against the hub proteins, and results were compared to their respective co-crystallized ligands. Results: Molecular docking indicated that major phytochemicals from PN exhibited significant binding affinities across all 10 hub host targets, typically outperforming or closely matching their respective co-crystallized ligands. The strongest contacts were observed for β-sitosterol–PIK3CB (−14.2 kcal/mol) and oleanolic acid–SYK (−14.0 kcal/mol), which were significantly stronger than the co-crystallized ligands (−7.9 and −8.3 kcal/mol, respectively), indicating robust stabilization within catalytic and regulatory pockets. Procyanidin B2 toward HCK (−10.5 vs. −7.9 kcal/mol) and PIK3CA (−9.5 vs. −7.3 kcal/mol), quercetin toward PIK3R1 (−10.6 vs. −8.2 kcal/mol) and PTPN11 (−9.2 vs. −7.5 kcal/mol), rutin toward SRC (−10.5 vs. 7.8 kcal/mol), and diosgenin toward EGFR (−9.4 vs. 8.4 kcal/mol). Procyanidin B2 maintained robust multi-hydrogen bonding networks, demonstrating significant binding, despite STAT1 and STAT3 docking showing identical affinities to co-crystals. Conserved hydrogen bonds, π–cation interactions, and significant hydrophobic packing at ATP-binding clefts and regulatory domains supported these interaction patterns, indicating competitive suppression of host signaling nodes taken over by HBV. Conclusions: Together, these results demonstrate that the components of PN possess strong multitarget binding capabilities across the PI3K/AKT, JAK–STAT, SRC-family kinase, EGFR, and SYK pathways, supporting their potential repurposing as host-directed HBV therapeutics with the ability to impede immune evasion, viral persistence, and HBV-associated oncogenic progression. Full article