Objectives: The SARS-CoV-2 pandemic caused major morbidity, mortality, and economic disruption, highlighting the need to better understand zoonotic spillover risks posed by coronaviruses. We investigated whether archived human sera from forested Guinea contained evidence of prior exposure to coronaviruses antigenically related to known pathogenic human coronaviruses. Methods: Archived sera collected in 2017–2018 from wildlife hunter communities in Guinea were analysed using serological assays against spike glycoproteins from SARS-CoV, SARS-CoV-2, MERS-CoV, and seasonal human coronaviruses. Binding responses to receptor binding domains were also assessed, together with spatial and subgroup analyses. Results: Pre-pandemic sera showed IgG cross-reactivity to SARS-CoV, SARS-CoV-2, and MERS-CoV spike antigens. A distinct subgroup demonstrated strong binding to both SARS-CoV and MERS-CoV receptor binding domains. Conclusions: These findings highlight the utility of sero-epidemiology in identifying potential zoonotic spillover. However, further investigation is needed to identify these viruses and determine their homology to known pathogenic coronaviruses.
The 2026 Bundibugyo virus disease outbreak in the Democratic Republic of the Congo and Uganda, the first Ebola-related PHEIC caused by a species lacking a licensed vaccine, has been accompanied by an information crisis marked by conspiracy-driven violence against response teams and destruction of treatment centres. Understanding what populations actually seek to know during such events is essential for designing effective communication strategies, yet the content of public information demand during Ebola outbreaks has not been systematically characterised. We combined Google Autocomplete query extraction (7347 unique queries from 83 seed terms in English and French) with Google Trends temporal analysis across six Ebola outbreaks (2014–2026). The autocomplete suggestion landscape was dominated by risk quantification and transmission concerns. Google Trends temporal analysis showed moderate to strong co-movement between misinformation-related search terms and overall Ebola search interest (Spearman ρ = 0.359–0.697, nominal p < 0.001). Substantial differences emerged between the English-language and French-language suggestion sets: French-language suggestions contained six times more misinformation and conspiracy content (4.9% vs. 0.8%) and nearly nine times more fear-related content (3.5% vs. 0.4%) than English-language suggestions. These findings demonstrate that infodemic management strategies designed in Anglophone contexts are inadequate for the populations most at risk and should inform linguistically adapted interventions for the ongoing response.
Background: Late presentation and poor immunovirological outcomes persist among people living with HIV (PLWH). The differential impact of HIV-1 subtypes on baseline disease presentation in antiretroviral therapy (ART)-naïve individuals remains incompletely characterized, particularly in regions dominated by unique recombinant forms. Methods: We conducted a retrospective cross-sectional study involving ART-naïve newly diagnosed PLWH at our hospital from January 2020 to October 2025. Immunological (CD4+, CD8+ T-cell counts, and CD4+/CD8+ ratios), biochemical [albumin (ALB), alanine aminotransferase (ALT), aspartate aminotransferase (AST)], virological (HIV-1 subtype, genotypic drug resistance), and clinical (admission type, age) parameters were analyzed. Multivariate linear regression identified factors independently associated with CD4+ T-cell count, CD4+/CD8+ ratio, and ALB level. Results: The study population comprised 762 ART-naïve newly diagnosed PLWH who were predominantly male (87.5%), older (median age 59), and presented with advanced immunosuppression (median CD4+ count 100 cells/µL). CRF07_BC was the dominant subtype (57.4%). Significant subtype-specific differences were observed: CRF01_AE infection was associated with the lowest CD4+ counts (median 54 cells/µL, p = 0.0004) and CD4+/CD8+ ratios (p = 0.0005). Inpatient status, indicating more severe presentation, was independently associated with significantly lower CD4+ counts (β = −36.91, p < 0.0001) and ALB levels (β = −7.358, p < 0.0001). Contrary to typical immune aging, patients aged ≥50 years had higher CD4+ counts at diagnosis (105.5 vs. 74 cells/µL, p = 0.0039). Genotypic drug resistance (22.2% prevalence) showed no independent association with baseline immunological status. Conclusions: Our findings reveal a distinct profile of late HIV presentation in a contemporary Chinese cohort, characterized by advanced age and the predominance of CRF07_BC. The independent association of inpatient status, rather than HIV-1 subtype or drug resistance, with severe immunosuppression and hypoalbuminemia highlights clinical presentation as the paramount indicator of baseline disease severity. The unexpected immunological advantage in older adults warrants further investigation.
Canine parvovirus 2 (CPV-2) is a major pathogen causing acute haemorrhagic enteritis and myocarditis in dogs. Since the discovery in the late 1970s, the original CPV-2 strain has evolved through VP2 mutations into new subtypes CPV-2a, 2b, and 2c. The viruses pose a persistent threat to canine health worldwide. This review summarizes the innate immunity evasion tactics employed by CPV-2, focusing on the interactions of various viral proteins and host signaling pathways. CPV-2 regulates the activation and inhibition of Toll-like receptors (TLRs), thereby influencing the downstream MyD88/TRIF signaling pathway and modulating the activation of NF-κB and interferons. CPV-2 exerts bidirectional regulation of apoptosis, thereby modulating host innate immune responses and promoting viral replication. CPV-2 employs multiple strategies to evade the humoral and adaptive immune systems, including evolutionary escape through rapid replication and the accumulation of mutations. Clarifying the key mechanisms underlying the defective TLR activation, the immunomodulatory functions of CPV proteins, and cross-species transmission of CPV-2 among animals and the potential zoonotic risk to humans can provide a crucial theoretical basis for precise virus control, understanding immune evasion, and assessing zoonotic risks, with significant value for both vaccine development and basic research.
Tick-associated viruses are an underexplored component of global viromes, and highly divergent RNA viruses often remain undetected due to low abundance and sequence divergence. Tacheng tick virus 8 (TcTV8) is a poorly characterized RNA flavivirus-like virus originally reported from Dermacentor-associated ticks in China, with few subsequent reports and no confirmed detections outside Asia. Here, we report the detection and partial genomic characterization of a TcTV8-like virus in ticks collected from Portugal. Sequence-independent (SISPA) nanopore sequencing of individual ticks recovered three partial fragments (~2.7 kb, ~14% of the reference genome; ~30% of the reference covered at ≥1×), which shared high amino-acid identity with the TcTV8 polyprotein, including a methyltransferase-region domain. Phylogenetic analysis placed the Portuguese sequence within the TcTV8 lineage. Read-level classification and coverage analysis further support the presence of this virus in the positive sample. These findings represent, to our knowledge, the first detection of a TcTV8-like virus in European ticks, extending its known geographic range beyond Asia. The detection of this cryptic viral lineage highlights the need for broader tick virome surveillance to better understand the diversity, evolution, and ecology of flavivirus-like viruses.
Mycoviruses represent promising tools for the biological control of phytopathogenic fungi. However, their application is often constrained by host specificity and low natural prevalence in certain pathogens. Fusarium verticillioides, a major maize pathogen and fumonisin B1 (FB1) producer, harbors very few known mycoviruses, a circumstance that limits the development of virus-based control strategies. In this study, we explored a virocontrol approach for F. verticillioides based on the use of a heterologous mycovirus, Cryphonectria hypovirus 1 (CHV1). For the artificial transfection of F. verticillioides with CHV1, we used an infectious cDNA clone of the virus and protoplast-mediated transformation. Through RT-PCR and double-stranded RNA (dsRNA) purification by chromatography on cellulose, it was confirmed that the CHV1 infectious cDNA clone is stably integrated into the fungal genome, giving rise to autonomous virus replication in the cytoplasm of F. verticillioides cells. Characterization of four independent transformants harboring CHV1 showed a significant reduction in FB1 production compared to the parental uninfected strain and only moderate alterations in vegetative growth. The CHV1-associated reduction in FB1 was confirmed in maize grown under both greenhouse and field conditions. Our findings provide evidence that heterologous mycoviruses can modulate mycotoxin production in F. verticillioides, thus expanding the pool of viral species that can be explored as potential biocontrol agents in this pathogen. Further work will be required to elucidate the underlying mechanisms of CHV1-associated downregulation of FB1 production in F. verticillioides and assess its potential application in virocontrol strategies.
Marine viruses are important components of microbial communities and influence their structure and dynamics, yet their variability remains poorly documented in the northwestern Arabian Gulf. Virus-like particle (VLP) abundance was monitored over four years at three coastal sites representing different environmental settings in Kuwait. Surface and depth samples were collected during each sampling period, along with physicochemical and nutrient data. VLP abundance fluctuated throughout the study and differed among sites and between depths. VLP counts tended to be higher at the southern site and near the surface, while the lowest values were recorded in Kuwait Bay. The three sites had distinct environmental characteristics, but relationships between VLP abundance and individual physicochemical variables varied among sites and seasons. When environmental, spatial, and temporal variables were considered together, Random Forest identified season, dissolved oxygen, and nutrients, particularly nitrate, among the important predictors of VLP abundance. Dissolved oxygen showed a nonlinear association with VLP abundance in the generalized additive model (GAM), and lower abundance at depth remained significant after accounting for the measured environmental variables, while site effects were not significant in this model. Overall, VLP abundance showed marked spatial and temporal variability across Kuwait coastal waters, with patterns associated with multiple environmental and seasonal factors. This four-year record provides a baseline for viral abundance in the northwestern Arabian Gulf and supports further investigation of the biological and environmental processes influencing viral dynamics in this highly variable coastal system.
Human metapneumovirus (hMPV) represents a leading cause of both upper and lower respiratory tract infections among children and adults globally. To investigate the prevalence and evolution of hMPV in the Jiaxing area of China between 2023 and 2025, we screened 3600 pharyngeal swab specimens by real-time PCR, identified 101 positives, and obtained genomic sequences of 48 viral isolates using high-throughput sequencing. Using the sequencing data, we reconstructed a phylogenetic tree and examined amino acid substitutions. The epidemiological analysis revealed an overall hMPV positivity rate of 2.81% (101/3600) in Jiaxing during 2023–2025. Although positive cases were detected across all age groups, they were mainly children, with no significant difference between genders. Regarding seasonal patterns, the peak of hMPV activity occurred predominantly during winter and spring. Over the study period, four genotypes co-circulated, in the order of B2 (41.67%), A2.2.2 (37.50%), A2.2.1 (16.67%), and B1 (4.17%). Further phylogenetic analysis showed that the B1 strains from Jiaxing clustered primarily with those from Beijing, China, while B2, A2.2.1, and A2.2.2 strains were more closely related to strains from the United States and Beijing. Of note, an A2c111nt-dup variant was identified in Jiaxing in 2023. Starting from November 2024, the prevailing genotype transitioned from A2.2.1/A2.2.2 to B2, and B2 emerged as the absolutely dominant strain by 2025. In comparison with earlier circulating strains, several amino acid substitutions have accumulated in current isolates, such as T223N, D280N, I392T, R396Q, S444N, K450R, and T521A in the F protein of B2 strains. Furthermore, the G, L, P, and SH proteins also displayed temporally patterned amino acid replacements. While the biological significance of these mutations is yet to be determined, these results highlight the public health importance of ongoing hMPV surveillance and dynamic monitoring of its genetic evolution.
The H9N2 avian influenza virus (AIV) is currently widespread globally and poses a serious threat to the poultry industry and public health; however, its global epidemiological characteristics and key molecular mutation patterns have not yet been systematically elucidated. Based on the NCBI Influenza Virus Resource Database, this study collected relevant data on the H9N2 AIV from around the world between 1966 and 2023. It conducted a comprehensive analysis of the geographic distribution of 11,933 strains, the temporal distribution of 11,824 strains, the host sources of 11,756 strains, and the genetic polymorphisms at key functional sites. The results showed that 90.14% of H9N2 AIV sequences in the dataset originated from Asia, with China contributing the largest number of sequences. The global sequence availability pattern underwent four phases: sporadic sequence availability, gradual increase, high sequence availability, and subsequent decline, with 2007–2018 representing a period of relatively high availability of publicly accessible sequences. Host analysis indicated that H9N2 AIV sequences were predominantly derived from poultry-related hosts, with chickens being the main host source in the dataset, and available sequences have also been reported from various mammals, including pigs and humans, as well as environmental media. Molecular analysis revealed that receptor-binding-related sites in the HA protein, such as Q226L and I155T, have become dominant variants, while mammalian-adaptive mutations such as PB2 E627K and D701N remain at low frequencies; M2 S31N is widely prevalent, whereas the detection rate of NA drug-resistance-associated mutations is low. This study systematically reveals the global distribution patterns of available H9N2 AIV sequences, host distribution characteristics, and key molecular mutation patterns of the H9N2 AIV, providing a scientific basis for cross-host transmission risk assessment, molecular surveillance, and targeted prevention and control.
Japanese encephalitis (JE) is a natural zoonotic disease caused by the Japanese encephalitis virus (JEV), which poses potential threats to human health and the pig farming industry. To establish infection, JEV must overcome the innate immune responses and complete its lifecycle in new hosts. Notably, the direct virus-induced neuronal cell death and an uncontrolled neuroinflammatory response jointly lead to the pathogenesis of JEV. In this review, we will focus on the innate immune response to JEV infection and the viral immune evasion strategies, such as escaping recognition or inhibiting the production of antiviral factors. Generally, JEV exploits four innate immune pathways, including type I interferon, interleukins, programmed cell death, and autophagy, to facilitate self-replication or exacerbate disease. Moreover, host microRNAs modulated during JEV infection have emerged as key regulators of this virus–host interplay. Therefore, a full understanding of how the immune system reacts to JEV infection and how the virus evades innate immune clearance will help develop effective vaccines or antiviral therapies.
The continued evolution of SARS-CoV-2 has reduced the protective effectiveness of first-generation vaccines and underscores the need for broadly reactive next-generation vaccine candidates. Here, we evaluated STFKB, an alum-adjuvanted bivalent recombinant protein vaccine composed of the monomeric Spike (STFKprototype) and the engineered Spike (STFK1628X). We assessed the immunogenicity, tolerability, and protective efficacy of STFKB in mice, rats, guinea pigs, rhesus macaques, and Syrian hamsters. STFKB induced robust STFK- and STFK1628X-specific antibody responses and broadly reactive neutralizing antibodies against multiple SARS-CoV-2 variants in the tested animal models. In hamster challenge studies, STFKB vaccination protected animals from Omicron BA.1 and BA.5 challenge, as shown by reduced body-weight loss, lower viral RNA loads in respiratory tissues, and improved gross lung pathology. Across the tested preclinical models, STFKB was well tolerated, with no vaccine-related overt toxicity observed under the study conditions. These findings support the rationale and translational potential of the bivalent vaccine strategy proposed in this study.
Crimean–Congo Hemorrhagic Fever Virus (CCHFV) is a tick-borne bunyavirus with widespread and growing geographic distribution that causes severe hemorrhagic fever and death. Vaccine candidates targeting the viral nucleoprotein (NP) have shown efficacy in both mouse and non-human primate models but the mechanism of protection is unclear. Here we employ the closely related Hazara virus (HAZV) to investigate how the intracellular antibody receptor TRIM21 uses anti-NP antibodies to neutralize infection. We show that TRIM21 can detect incoming NP particles within hours of infection and that this results in a potent block to infection. Electroporated-antibody-dependent neutralization assay (EDNA) experiments reveal that TRIM21 inhibits viral transcription, protein expression and genome synthesis and reduces the production of infectious virions. Mutations and domain deletions within TRIM21 reveal that neutralization requires antibody-binding by the PRYSPRY domain but is only partially dependent on the E3 ubiquitin ligase RING domain. The data suggest a dual restriction mechanism in which NP cross-linking by TRIM21 physically interferes with NP function whilst parallel ubiquitination labels the protein for degradation. This dual mechanism is similar to that used by TRIM5 against retroviruses and suggests that antiviral TRIMs may utilize their capacity for self-assembly both for catalytic activation and viral caging.
Potato virus X (PVX) is an economically important pathogen of potato (Solanum tuberosum), causing global yield losses of 30–40% annually in single infections and up to 80% in mixed infections. To analyze genetic diversity and evolution, 413 full-length PVX isolates available in the databases were investigated. Pairwise nucleotide sequence identities using the Sequence Demarcation Tool (SDT) suggested a tentative, dataset-dependent species and strain demarcation threshold of 76% and 89%, respectively, delineating eleven (11) putative strains, named alphabetically from A to K. Phylogenetic analysis strongly supported the provisional strain demarcation, showing distinct and non-overlapping phylogenetic clusters. PVX-A constitutes a phylogenetically heterogeneous lineage, potentially contributing to its evolutionary success and long-term persistence. The PVX population exhibited high nucleotide and haplotype diversity, elevated gene flow and a moderate level of genetic differentiation among the geographically distinct clusters. Recombination analysis, using RDP, identified 20 recombination events involving 50 recombinant isolates, while the GARD program detected only a single breakpoint at position 6229 bp within the coat protein (CP) region. Recombination, alongside the nucleotide substitution rate and gene flow, was identified as a secondary evolutionary force driving PVX diversity. The Andean region was identified as the probable origin of PVX, from which it spread to Europe through early transcontinental human activities and subsequently disseminated across the world. The Andes and Europe likely represent two major evolutionary niches. PVX has a moderate host range, with potato as its prime natural host, and the majority of PVX genotypes infect only potato. Among all PVX genomic lineages, PVX-A shows the widest geographical distribution and host range, reported in almost every potato-growing country, including Pakistan. This study provides a comprehensive framework for understanding PVX diversity, provisional strain demarcation, evolution, and global dispersal, facilitating acquiring sustainable resistance and improving preventive strategies against PVX for global potato cultivation.
Hemorrhagic fever with renal syndrome (HFRS), caused by Seoul orthohantavirus (SEOV) and Hantaan orthohantavirus (HTNV), remains a neglected rodent-borne zoonosis with persistent residual spillover risk in low-incidence regions of China. This study assessed human HFRS occurrence and small-mammal hantavirus surveillance signals in small-mammal hosts across Zhejiang Province, China, in 2025. Reported human cases were obtained from the National Notifiable Disease Surveillance System, and animal host surveillance was conducted at five designated monitoring sites. A total of 107 HFRS cases were reported, occurring year-round with peaks in June and December and showing spatial heterogeneity, presenting a predominance of males, adults aged ≥40 years, and farmers. Animal host surveillance captured 617 small mammals (566 rodents and 51 shrews) from 15,457 valid trap-nights, with Apodemus agrarius (30.31%) and Rattus norvegicus (29.98%) as the dominant species. Sixteen animals were positive for hantavirus RNA and/or antibody, including 12 for hantavirus RNA and 6 antibody-positive animals; two were positive for both markers. Positive animals were detected in multiple species, including Niviventer confucianus, R. norvegicus, Rattus losea, A. agrarius, Suncus murinus, and Rattus tanezumi. Human incidence, small-mammal density, host species composition, and hantavirus-positive rates were not fully concordant across surveillance sites. Our findings reveal sustained cryptic orthohantavirus circulation in low-endemic Zhejiang, highlighting that integrated human-reservoir One Health surveillance is indispensable for precise spillover risk prediction and targeted zoonotic disease intervention.
By combining next-generation sequencing (NGS), reverse transcription polymerase chain reaction (RT-PCR), and rapid amplification of cDNA ends (RACE) PCR, we sequenced from adult bean flower thrips (Megalurothrips usitatus) the near-complete genome of a previously undescribed virus (related to Anopheline-associated C virus), which we named “Megalurothrips usitatus associated virus 1” (MUaV1). The viral genome comprises two linear, single-stranded, positive-sense RNA segments, designated RNA1 (3658 nt) and RNA2 (2041 nt), which shared 35.75% and 23.74% nucleotide identity with Anopheline-associated C virus (YP_009011225.1) and chronic bee paralysis virus (ASM62179.1), respectively. According to phylogenetic analysis, MUaV1 shares the closest evolutionary relationship with Anopheline-associated C virus, followed by chronic bee paralysis virus. A clear predominance of 22 nt vsiRNAs, characteristic of Dicer-mediated siRNA processing in insects, was observed, demonstrating that MUaV1 is capable of infecting the bean flower thrips and activating its antiviral RNAi response. Our study provides the first characterization of this virus in the bean flower thrips, enhancing our understanding of the bean flower thrips virome.
Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic gammaherpesvirus that causes Kaposi’s sarcoma (KS), an endothelial cell-derived malignancy that primarily affects immunocompromised individuals. During lytic reactivation, KSHV expresses viral proteins that promote viral replication and modulate host signaling pathways. Here, we identified the calcium-activated chloride channel ANO1 (TMEM16A) as a previously unrecognized host factor induced by the KSHV lytic protein vGPCR. RNA sequencing, RT-qPCR, and immunofluorescence analyses demonstrated robust ANO1 upregulation in vGPCR-expressing endothelial cells and during KSHV lytic reactivation. siRNA-mediated depletion of vGPCR significantly reduced ANO1 expression, demonstrating that vGPCR contributes to ANO1 induction during infection. Functionally, ANO1 knockdown sensitized vGPCR-expressing endothelial cells to caspase-dependent apoptosis under serum-starved conditions, which was rescued by the pan-caspase inhibitor Z-VAD-FMK. In reactivated iSLK.BAC16 cells, genetic or pharmacological inhibition of ANO1 increased late apoptosis, enhanced KSHV lytic gene expression, and promoted infectious virion production. Together, these findings identify ANO1 as a vGPCR-regulated host factor that promotes cell survival and modulates KSHV lytic replication, highlighting ANO1 signaling as a potential therapeutic target in KSHV-associated disease.
Herpes simplex encephalitis (HSE) remains a life-threatening disease with high mortality and severe neurological complications, despite acyclovir therapy being limited by delayed diagnosis, drug resistance, and poor blood–brain barrier penetration. New antivirals with different mechanisms of action are urgently needed. We evaluated PDSTP, a novel dispirotripiperazine-based compound targeting host heparan sulfate proteoglycans (HSPGs), in mouse models of HSV-1 encephalitis. This study evaluates the therapeutic and prophylactic potential of PDSTP, an antiviral compound that blocks HSV glycoconjugates on the host cell membrane, using a well-established mouse model of herpes encephalitis. BALB/c mice were infected with HSV-1 strains VR-539 or VR-733 via intraperitoneal (IP) or intranasal (IN) routes. PDSTP was administered orally (PO) or intraperitoneally (IP) at 12.5–80 mg/kg/day, alone or in combination with acyclovir (10–100 mg/kg/day), using a prophylactic–therapeutic regimen (2 h pre-infection, then twice daily for 7 days). Survival, weight loss, mean survival time, and brain viral loads were assessed. PDSTP at 80 mg/kg/day (PO) protected 30–40% of VR-733-infected mice and extended lifespan 1.9-fold (p < 0.05), comparable to acyclovir at 100 mg/kg/day. IP administration was superior to PO. The combination of IP PDSTP (12.5 mg/kg/day) with IP acyclovir (10 mg/kg/day) achieved 100% survival, prevented weight loss, and significantly reduced brain viral titers (p < 0.001) in both infection models. PDSTP demonstrates dose- and strain-dependent activity as monotherapy and enhanced efficacy when combined with acyclovir. The IP combination provided complete protection at low doses, supporting PDSTP as a promising candidate for further development against HSE.
The persistent global threat posed by emerging and re-emerging RNA viruses, including SARS-CoV-2, influenza A(H1N1)pdm09, DENV-2, and CHIKV, highlights the critical need for novel and broad-spectrum antiviral agents. Building upon the established antiviral activity of the quinoline scaffold, this study employed a molecular hybridization strategy to design and synthesize a novel series of 1,2,3-triazole–quinoline derivatives (compounds 4a–4h). This approach strategically fused the bioactive quinoline nucleus with the pharmaceutically favorable 1,2,3-triazole ring. The new compounds were synthesized efficiently in three steps with moderate-to-high yields, and their structures were subsequently determined. Their inhibitory capacities against the four viruses and cytotoxicity across relevant cell lines were evaluated in vitro. The initial screening demonstrated that compounds 4a–4h possessed broad-spectrum antiviral activity, showing high inhibition percentages at 10 µM against SARS-CoV-2, DENV-2, and CHIKV. Notably, compounds 4c and 4e, substituted with methoxy and ethyl groups, respectively, displayed exceptional potency and safety against SARS-CoV-2, yielding high selectivity indices (SI: 1896.5 and 1265.8, respectively). Furthermore, in silico absorption, distribution, metabolism, and excretion (ADME) and molecular docking calculations suggested favorable drug-likeness profiles, including improved lipophilicity and non-P-glycoprotein substrate feasibility. The findings validate the molecular hybridization strategy, establishing this new class of compounds as promising, multi-target antiviral prototypes for further preclinical exploration against prevalent viral pathogens.
Viral proteases process viral polyproteins into functional proteins and are therefore essential for viral replication and antiviral drug development. Most research has focused on mature enzymes, whereas precursor and partially processed protease forms remain poorly understood. This review examines viral protease maturation as a dynamic and temporally regulated process. Immature precursors are often membrane-associated and conformationally heterogeneous, and their activation is controlled by mechanisms such as cis cleavage, dimerization, cofactor binding, and interdomain communication. These regulatory steps represent potential vulnerabilities in production of viral progeny. We discuss how conformational dynamics influence protease maturation in coronaviruses, flaviviruses, picornaviruses, and retroviruses, and how defined precursor states may be pharmacologically exploited. Targeting these states could complement inhibition of the mature enzyme, increase the barrier to drug resistance, or dysregulate maturation by inducing premature protease activation, thereby disrupting viral particle production. Protease maturation therefore offers a conceptual framework for antiviral strategies that extend beyond classical active-site inhibition.
Tuberculosis (TB) is a leading global cause of infectious disease. Growing evidence suggests that TB significantly increases the risk of comorbidity in HIV+ patients, particularly acute ischemic stroke (AIS). Prognosis is often poor, highlighting the need for early prevention and intervention. However, exact mechanisms linking HIV-Mtb coinfection and stroke remain poorly understood. A review of articles from 2016 to 2026 was conducted to study the risk of ischemic stroke and treatment strategies in HIV-Mtb coinfection. Both HIV and Mtb can increase stroke risk, but pathogenesis of the coinfection and relationship between the coinfection and stroke remain as proposals. Antiretroviral therapy (ART) has shown variable success rates; it may increase the risk of stroke or be associated with worse outcomes. Multi-drug-resistant TB (MDR-TB) can be treated with a combination of bedaquiline, linezolid, and pretomanid (BPaL). Steroids and vitamin D supplementation with ART are associated with improved outcomes. For coinfection screening, the monocyte-to-lymphocyte ratio (MLR) and a clinical scoring system for triage may prove useful for early detection, leading to prompt intervention. A clearer understanding of the association between HIV-Mtb coinfection and stroke is essential for developing effective prevention strategies and eliminating transmission. Advancement of current treatments will help improve long-term outcomes in HIV-Mtb coinfection.
