Search Results (278)

Human immunodeficiency virus (HIV) is an enveloped virus with a remarkable capacity for genetic diversification, enabling rapid escape from host immune responses and therapeutic interventions. Despite extensive global efforts, the development of an effective vaccine has remained elusive owing to the virus’s high genetic variability and antigenic diversity. Consequently, considerable effort has been directed toward the development of therapeutic agents targeting viral entry, reverse transcriptase, integrase, protease, and more recently, capsid. Although antiretroviral therapy (ART) remains the cornerstone of HIV treatment, it is associated with challenges including drug resistance, adverse side effects, and limitations in access and affordability. Targeting viral entry offers distinct advantages by blocking infection at the earliest stage of the viral life cycle and enabling the neutralization of free virions, as well as Fc-mediated elimination of HIV-infected cells in some cases. This review highlights promising protein-based HIV entry inhibitors that have demonstrated efficacy in preclinical studies, and discusses ongoing efforts to optimize their valency, avidity, specificity, serum half-life, effector functions, and production platforms to improve their therapeutic potential and economic feasibility. Full article

Chalcones are naturally occurring open-chain flavonoids widely distributed in plants and recognized for their broad spectrum of pharmacological activities. Their versatile scaffold allows for extensive structural modifications, leading to a diverse range of natural and synthetic derivatives with notable biological potential. In the context of viral infections, chalcones have demonstrated remarkable efficacy against a variety of human pathogens, including dengue virus, HIV, HCV, influenza A, SARS-CoV-2, and other emerging viruses. Beyond human health, several chalcones have shown potent activity against plant viruses such as tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV), and animal viruses including porcine reproductive and respiratory syndrome virus (PRRSV) and mammalian reovirus (MRV), underscoring their broad antiviral spectrum. These compounds act through multiple mechanisms, including the inhibition of viral enzymes (e.g., proteases, polymerases, and integrases), interference with viral entry and replication, and the modulation of host-related pathways. Recent advances in molecular docking, structure–activity relationship (SAR) studies, and synthetic optimization have further highlighted chalcones as a promising scaffold for antiviral drug discovery. Accordingly, this review summarizes and categorizes antiviral chalcones reported over the last two decades, emphasizing and critically discussing their molecular targets, mechanisms of action, and pharmacological potential as lead compounds. It also provides a comparative perspective on their pharmacological relevance by correlating their activities against standard therapeutic agents and reference inhibitors. Furthermore, the most recurrent viral targets were critically discussed regarding their conservation, expected genetic barriers to resistance, and the global SAR trends identified for the corresponding antiviral chalcones. Finally, in silico ADMET profiling of the most promising naturally occurring chalcones was performed to evaluate their drug-likeness and pharmacokinetic properties, offering guidance for future structural optimization and translational development. Collectively, these findings highlight the chalcone scaffold as a versatile platform for the development of novel antiviral agents targeting diverse viral and host pathways. Full article

Human viral entry receptor mouse models exist to overcome a fundamental experimental barrier: many clinically important viruses bind their human entry factors far more efficiently than the corresponding murine orthologs, leaving conventional mice unable to support authentic infection, physiological tissue tropism, or meaningful countermeasure evaluation. This review is organized around the receptor-humanization concept rather than around a single coronavirus model. Engineering strategies compared here include random transgenesis, endogenous-locus knock-in, minimal receptor-interface humanization, conditional and inducible expression, and transient vector-mediated delivery. Receptor systems covered span human angiotensin-converting enzyme 2 (hACE2)-dependent sarbecoviruses, human dipeptidyl peptidase 4 (hDPP4)-dependent Middle East respiratory syndrome coronavirus (MERS-CoV), human cluster of differentiation 4/human C-C chemokine receptor type 5 (hCD4/hCCR5)-dependentt human immunodeficiency virus type 1 (HIV-1), adenovirus receptor models, human intercellular adhesion molecule 1 (hICAM-1) rhinovirus systems, hepatitis C virus (HCV), hepatitis B virus (HBV), and hepatitis D virus (HDV) entry-factor models, measles receptor models, poliovirus receptor/CD155 (PVR/CD155) models, human scavenger receptor class B member 2 (hSCARB2) enterovirus systems, and human transferrin receptor 1 (hTfR1) arenavirus models. We then discuss how these platforms support antibody evaluation, Fc-effector analysis, vaccine protection, variant benchmarking, and safety assessment. These models yield the most reliable data when the experimental question is explicitly entry-dependent and when receptor expression level, anatomical distribution, pathology window, and immune context have all been independently validated. They are least informative when receptor expression is non-physiological, when disease readouts are driven by promoter artifacts, or when post-entry species barriers remain the dominant bottleneck. A validation-centered framework is therefore proposed to guide the selection of each model for the specific antiviral antibody or vaccine question it can legitimately answer. Full article

Determining HIV-1 tropism provides the prognosis of HIV infection and is required before prescribing maraviroc, an entry inhibitor that blocks the interaction between the viral gp120 and the CCR5 coreceptor. However, existing prediction algorithms have been developed primarily for the globally most prevalent subtypes (B, C, and CRF01_AE) and often show reduced performance for other HIV-1 genetic variants. Sub-subtype A6 and circulating recombinant form CRF63_02A6 dominate the HIV-1 epidemic in Russia and other Former Soviet Union (FSU) countries, yet the reliability of tropism prediction for these viruses remains virtually unexplored. We phenotypically determined the tropism of 25 clinical isolates (11 R5, 1 X4, and 7 dual-tropic R5/X4) using U87.CD4.CCR5 and U87.CD4.CXCR4 cell lines and performed a comparative analysis of eight existing genotypic tools (Geno2pheno, WebPSSM, T-CUP 2.0, the Delobel/Garrido rules, and others) or their modifications on a combined dataset that included Los Alamos National Laboratory (LANL) reference sequences (subtypes A, B, C, CRF01_AE, and CRF02_AG) and our laboratory-derived isolates. Most models achieved high accuracy for globally prevalent subtypes (≈95% for B, C, and CRF01_AE) but showed markedly reduced performance for sub-subtype A6 (best accuracy among existing models, 85%) and CRF63_02A6 (best accuracy, 72%), with a poor balance between sensitivity and specificity. To address this problem, we developed HIV-V3Augur, an ensemble stacking model based on the Random Forest and Support Vector Machine (SVM) machine learning algorithms, trained on Pseudo Amino Acid Composition (PseAAC) and Relative Synonymous Codon Usage (RSCU) features with 10-fold stratified cross-validation. HIV-V3Augur achieved an accuracy of 77%, sensitivity of 79%, and specificity of 79% on sub-subtype A6, and on CRF63_02A6 it reached an accuracy of 95%, sensitivity of 87%, and specificity of 100%. Cross-validation demonstrated that HIV-V3Augur represents a balanced genotypic tropism prediction tool for understudied HIV-1 variants circulating in the FSU region. HIV-V3Augur can be used locally through a graphical user interface. Full article

Objectives: Membrane-enveloped virus-like particles (VLPs) constitute a versatile vaccine platform allowing for the display of heterologous viral surface antigens. The density of displayed antigens is paramount for the efficient elicitation of a strong cellular and humoral immune response. SARS-CoV-2 spike protein variants with engineered cytoplasmic tails (CTs) were generated to enhance decoration efficiency on the surface of VLPs formed by the HIV core protein Gag. These HIV (SARS-CoV-2) chimeric particles serve as a vaccine component prototype. Methods: Spike variants were first analyzed for cellular and surface expression as well as incorporation into extracellular vesicles (EVs) and VLPs using flow cytometric analysis and Western blot analysis. Receptor binding, fusogenicity, i.e., mediating the fusion of spike-positive with receptor-containing membranes, and the proteins’ potential to mediate lentiviral vector gene transduction into susceptible target cells was examined by employing syncytia-formation assays and vector titration experiments. The display of a neutralization-sensitive epitope was examined utilizing immuno-precipitation using a neutralizing antibody. Results: All four variants were shown to be cell-surface expressed, to recruit the cognate receptor, to mediate membrane fusion and cell entry of lentiviral pseudotype vector particles and to decorate VLPs and EVs. However, the spike variant encompassing a truncated CT derived from the gibbon ape leukemia virus (GaLV) transmembrane (TM) envelope protein was most efficiently incorporated into HIV Gag-formed VLPs. All variants exposed a neutralization-sensitive epitope in the receptor binding domain. Conclusions: Engineering of the CTs of viral surface antigens can enhance VLP decoration, while required functionality of the ecto-domain such as receptor recognition, fusogenicity and neutralization-sensitive epitope presentation are not abrogated. This indicates the preservation of the structural integrity of the antigen required to elicit a neutralizing humoral immunity upon vaccination. The identified truncated CT of GaLV TM may be of utility to improve the incorporation of other viral surface antigens into a variety of membrane-enveloped VLPs derived from a range of different parental viruses. Full article

A within-host HIV dynamics model incorporating latent reservoirs, distributed time delays, and a B-cell-mediated humoral immune response is developed and analyzed mathematically. The model includes five compartments: uninfected CD4⁺ T cells, latently infected cells, actively infected cells, free virions, and B cells. Four distinct distributed delays are introduced to account for the periods between viral entry and the emergence of latently or actively infected cells, reactivation of latently infected cells, and intracellular virion production. For the non-delayed system, the basic reproduction number ${\mathcal{R}}_0$ is derived using the next-generation matrix method. Using Lyapunov functions and LaSalle’s Invariance Principle, a sharp threshold dynamic is proven: the infection-free equilibrium is globally asymptotically stable (GAS) when ${\mathcal{R}}_0\le 1$, whereas a unique endemic equilibrium is GAS when ${\mathcal{R}}_0>1$. For the full distributed-delay system, a delay-dependent reproduction number ${\mathcal{R}}_0^d$ is defined. The global asymptotic stability of the infection-free equilibrium is established for ${\mathcal{R}}_0^d\le 1$, and the global asymptotic stability of the endemic equilibrium is established for ${\mathcal{R}}_0^d>1$, using suitably constructed Lyapunov functionals that account for the delay history. Numerical simulations validate the analytical threshold behavior. A sensitivity analysis of ${\mathcal{R}}_0^d$ identifies the most influential parameters for potential intervention. A treatment-dependent reproduction number is derived, and the critical drug efficacy required for viral eradication is determined. The intracellular production delay is shown to act as a critical threshold for infection clearance. Full article

Mpox is a rare but potentially serious vaccine-preventable disease. The 2022 United States outbreak disproportionately impacted gay, bisexual, and other men who have sex with men, people living with HIV, and people of transgender experience. Early vaccination efforts revealed substantial racial and geographic inequities, with lower uptake among Black and Hispanic cisgender men, transgender women, and residents of rural areas. To address these challenges, Fairview’s Minnesota Immunization Networking Initiative (MINI), a 20-year-old mobile health collaborative, partnered with state and local public health agencies and community-based organizations to expand mpox vaccine access. With support from governmental outbreak response funding and stockpiled vaccine, mobile clinics were deployed in trusted community settings, including Pride events and recurring community sites. Targeted outreach, education, and coordination with local providers supported stigma reduction and second-dose series completion. Program data were collected from October 2022 through December 2024. MINI hosted 125 community-based mpox vaccination events, administered 2259 doses to individuals from 220 cities across the United States, including 195 cities in the Midwest. Pride events were key entry points for first-dose vaccination, particularly in rural areas; urban non-Pride clinics played a complementary role in facilitating second-dose completion. Program-level vaccination-to-case ratios were highest among populations experiencing disproportionate mpox burden, including Black, Hispanic, and American Indian/Alaska Native male participants, suggesting alignment of preventive resources with community need. MINI’s mobile, partnership-driven approach demonstrates the value of pairing large-scale community events with recurring clinics to address barriers to both vaccine access and series completion. These findings underscore the importance of flexible, community-centered infrastructure in advancing health equity and strengthening outbreak preparedness. 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

People living with HIV (PLWH) receiving effective antiretroviral therapy (ART) continue to exhibit chronic immune activation and systemic inflammation despite virological suppression. The viral envelope glycoprotein gp120, which binds the CD4 receptor and mediates viral entry, has been implicated in pro-inflammatory and pro-apoptotic effects in neuronal and endothelial cells. Although gp120 is expressed on the viral surface, its oligomeric structure and its ability to form immune complexes with circulating antibodies may reduce the sensitivity of standard detection assays in serum. Soluble gp120 has been associated with increased levels of pro-inflammatory cytokines, including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β), as well as chemokines. These mediators may contribute to blood–brain barrier dysfunction, endothelial injury, vascular smooth muscle alterations, and subsequent neurodegenerative and cardiovascular complications. Importantly, gp120 shedding may persist due to viral reservoirs and intermittent reactivation, even during ART. Fostemsavir inhibits the interaction between gp120 and CD4, preventing viral entry and potentially limiting gp120-mediated pathogenic effects. Beyond antiviral activity, this mechanism suggests a potential role in attenuating gp120-mediated inflammation. This review discusses the biological effects of gp120 and the rationale for targeting it therapeutically in PLWH. Full article

Interferon-induced transmembrane proteins (IFITMs) are broad-spectrum antiviral factors that restrict the entry of many enveloped viruses, including HIV-1, by modifying host membrane properties and trapping fusion at the hemifusion stage. Beyond blocking entry in target cells, IFITMs also reduce the infectivity of virions produced from IFITM-expressing cells, a phenomenon termed “negative imprinting”. Conserved motifs, such as the amphipathic helix and oligomerization motifs, have been reported to be essential for IFITM-mediated protection of target cells from viral infection. Yet, the impact of IFITM incorporation on progeny virion infectivity remains poorly defined. Here, we show that IFITM3 mutants defective in target cell protection activity still markedly impair HIV-1 fusion/infection upon incorporating into virions, without affecting viral maturation or Env incorporation. Immunofluorescence studies suggest mislocalization of the IFITM3 mutants as the reason for the lack of antiviral activity in target cells. Testing the antiviral activity of chimeras between antiviral and non-antiviral IFITM orthologs failed to clearly identify a domain responsible for reduction of HIV-1 infectivity, suggesting that multiple domains may be required for negative imprinting. Interestingly, co-incorporation of non-antiviral dog IFITM1 with human IFITM3 did not interfere with IFITM3’s negative imprinting activity, despite forming mixed hetero-oligomers. This finding implies a dominant, oligomerization-independent antiviral phenotype of IFITM3 in virions. Our findings suggest that IFITMs may protect target cells and negatively imprint progeny virions through distinct mechanisms, underscoring the need to further characterize the molecular basis for the reduced fusion competence of IFITM-containing HIV-1 particles. Full article

Marine ecosystems have yielded a remarkable diversity of bioactive metabolites with relevance for antiviral drug discovery. This article reviews recent advances in marine-derived compounds investigated as anti-HIV agents. Metabolites, such as sulfated polysaccharides, lectins, alkaloids, and terpenoids, display inhibitory activity across multiple stages of the HIV life cycle, including viral entry, reverse transcription, integration, and maturation. From sponge-inspired development of AZT to the application of Griffithin in clinical trials for the prophylaxis of the HIV infection, recent discoveries showcase the chemical diversity of marine ecosystems and validate their utility as hit and compound sources in drug discovery. We highlight possible mechanisms of action, as well as translational hurdles from research to clinical trials. Overall, marine biodiversity represents a valuable and underexploited reservoir for the development of novel HIV therapeutics. Full article

Glycan-mediated processes can be critical determinants of viral attachment and entry, yet for enveloped RNA viruses, including SARS-CoV-2, their mechanistic roles remain incompletely defined. This review synthesizes current structural and functional evidence for glycan engagement during SARS-CoV-2 attachment and entry. We describe the general viral entry pathways and their reliance on glycan recognition, followed by the interactions of the SARS-CoV-2 spike glycoprotein with host glycans, including ABO(H) blood group antigens, sialylated glycans, and endogenous lectins. Based on structural biology, glycobiology, and virology, we focus on how the spike protein exploits both glycan motifs and lectin receptors to enhance attachment, promote cellular uptake, or modulate host tropism. We contextualize these mechanisms by comparing glycan dependencies across other human viruses, including the influenza virus, HIV, and norovirus. Finally, we provide a comparative virological perspective to derive broad evolutionary insights into how enveloped viruses exploit the host glycans. Full article

HIV-1 entry into host cells culminates in integration of the reverse transcribed double-stranded viral DNA into host genes. Several lines of evidence suggest that intact, or nearly intact, HIV-1 cores—large, ~60 nm-wide structures—pass through the nuclear pore complex (NPC), and that this passage is associated with pore remodeling. Cryo-electron tomography studies support the dynamic nature of NPCs and their regulation by cytoskeleton and ATP-dependent processes. To explore NPC remodeling, we used super-resolution Stochastic Optical Reconstruction Microscopy (STORM) of U2OS cells endogenously expressing nucleoporin 96 tagged with SNAP. Single-molecule localization imaging and computational averaging resolved 8-fold symmetric nuclear pores with an average radius of ~51 nm. Depletion of cellular ATP using sodium azide or antimycin A, previously reported to reduce the size of yeast NPCs, did not significantly alter the nuclear pore radius in U2OS cells. Similarly, stressing the nuclear envelope by hypotonic or hypertonic conditions failed to induce detectable expansion or contraction of NPCs. These results indicate that the NPCs in U2OS cells do not respond to ATP depletion nor mechanical stresses on changes in pore morphology that can be resolved by STORM. Since these cells are infectable by HIV-1, we surmise that direct multivalent interactions between HIV-1 capsid and phenylalanine-glycine nucleoporins lining the pore’s interior drive the core penetration into the nucleus and the associated changes in the pore structure. Full article

Background: Human Immunodeficiency Virus type 1 (HIV-1) remains a major global health challenge. Despite advances in antiretroviral therapy, new prevention strategies are needed, particularly topical microbicides capable of blocking the earliest steps of viral entry. HIV-1 attachment relies on interactions with heparan sulfate proteoglycans on host cell surfaces; therefore, sulfated heparan-mimetic polymers have been explored as antiviral agents. In this context, sulfated chitosan microparticles are designed to mimic natural glycosaminoglycan receptors, acting as biomimetic decoys that prevent viral attachment and entry. Methods: Low-molecular-weight sulfated chitosan (LMW Chi-S) microparticles were synthesized and characterized (SEM, EDS, DLS, FTIR) following US Patent No. 11,246,839 B2. Their antiviral activity was evaluated by incubating the microparticles with high-viral-load HIV-1-positive plasma (~3.5 × 10⁶ copies/mL) to enable viral binding and removal by pull-down. The performance of the synthesized Chi-S microparticles was compared with established heparinoid controls, including soluble heparin and heparin microparticles. Results: Chi-S microparticles exhibited stronger virus-binding and neutralizing capacity than all heparinoid comparators, achieving up to 70% reduction in viral load relative to untreated HIV-1 plasma. In comparison, soluble heparin and heparin microparticles reduced viral load by approximately 53% and 60%, respectively. Subsequent evaluation across multiple tested concentrations confirmed a consistent antiviral effect, indicating that the synthesized Chi-S microparticles maintain robust virus–particle interactions throughout the concentration range examined. Conclusions: These findings demonstrate that LMW Chi-S microparticles possess potent antiviral properties and outperform classical heparinoid materials, supporting their potential application as topical microbicides targeting early HIV-1 entry mechanisms. Full article

Background: Survivin is an anti-apoptotic protein highly expressed during embryonic development and, in adults, mainly in the gastrointestinal epithelium. Its levels decrease in human gastric tissue and cultured cells upon exposure to Helicobacter pylori gamma-glutamyl transpeptidase (GGT), though the underlying mechanism remains unclear. Objective: We aimed to investigate the role of cap-independent translation driven by the Survivin 5′ untranslated region (5′UTR) in response to H. pylori infection in vitro. Methodology: Human cell lines (AGS, GES-1, HeLa, HEK293T) were used alongside bicistronic and monocistronic (Firefly/Renilla luciferases) reporter assays to assess short and long variants of the Survivin 5′UTR and HIV-1 internal ribosome entry site (IRES) sequences. Additional methods included in vitro transcription/translation, RT-qPCR, agarose gel electrophoresis, Western blotting, coupled/uncoupled translation assays, and siRNA silencing. Results: The short variant of the Survivin 5′ UTR supported cap-independent translation, like the HIV-1 IRES. Notably, H. pylori infection suppressed this translation in a GGT-dependent manner in gastric cells, and a similar reduction was observed following treatment with ATO, a known prooxidant. Conclusion: The Survivin 5′UTR exhibits cap-independent translation activity that is inhibited by H. pylori in a GGT-dependent manner, likely via oxidative stress. This mechanism helps to explain the downregulation of Survivin during gastric infection and indicates that oxidative stress can negatively affect both cellular and viral IRES-mediated translation. Full article