Search Results (457)

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

This review explores the interplay between SARS-CoV-2 and HIV-1 infections within the human brain, highlighting the significant neurological implications of these viral infections. SARS-CoV-2 can infect the central nervous system (CNS), with evidence of the virus detected in various brain regions, including the hypothalamus, cerebellum, and olfactory bulb. This infection is linked to microglial activation and neuroinflammation, which can lead to severe neurological outcomes in affected individuals. Autopsy studies revealed microglial changes, including downregulation of the P2RY12 receptor, indicating a shift from homeostatic to inflammatory phenotype. Similar changes in microglia are found in the brains of people with HIV-1 (PWH). In SARS-CoV-2, the correlation between inflammatory cytokines, such as IL-1, IL-6, and MCP-1, found in cerebrospinal fluid and brain tissues, indicates significant neurovascular inflammation. Astrogliosis and microglial nodules were observed, further emphasizing the inflammatory response triggered by the viral infections, again in parallel to those found in the brains of PWH. Epidemiologic data indicate that although SARS-CoV-2 infection rates in PWH mirror those in People without HIV (PWoH) populations, Long-COVID prevalence is markedly higher among PWH. Evidence of overlapping cognitive impairment, mental health burden, and persistent neuroinflammation highlights diagnostic complexity and therapeutic gaps. Despite plausible mechanistic synergy, direct neuropathological confirmation remains scarce, warranting longitudinal, biomarker-driven studies. Understanding these interactions is critical for developing targeted interventions to mitigate CNS injury and improve outcomes. Full article

Antiretroviral drugs are associated with increased body weight and metabolic disorders. Fat gain and insulin resistance are commonly associated with abdominal obesity in people with HIV (PWH). There is currently an open ongoing discussion about how antiretroviral therapy affects body weight and its significance in hunger–satiety circuit alteration. Until now, the impact of the drug on this circuit has not been explored. This study aimed to assess the hormones involved in appetite and satiety regulation in the serum and hypothalamus after efavirenz (EFV) administration in mice. EFV (10 mg/kg) and distilled water (1.5 μL/kg) (control group) were orally administered for 36 days to CD1 mice. Body weight and food intake were determined throughout treatment. At the end of the treatment, the metabolic profile (glucose, triglycerides, cholesterol) was assessed, and leptin, soluble receptor of leptin (sOB-R), and ghrelin were measured in serum; moreover, we evaluated the expression of growth hormone secretagogue receptor 1a (GHS-R1a), neuropeptide Y receptor 1 (NPYR1), and leptin in the hypothalamus, and a sucrose preference test (SPT) was conducted. Outcomes showed an increase in serum ghrelin and the expression of GHS-R1a and NPYR1 receptors in the hypothalamus, coinciding with an increase in appetite and preference for sucrose in mice in the EFV group. Furthermore, serum leptin, sOB-R, and the free leptin index (FLI) showed that hunger is not related to a lack of satiety. Despite increased food intake, a reduction in body weight was observed, and triglyceride and cholesterol levels were increased. According to our findings, mice treated with EFV showed a decrease in body weight, despite increased food intake resulting from appetite stimulation, which is caused by specific compounds, hormones, and neural signals acting on the brain’s hunger centres, primarily in the hypothalamus, promoting eating behaviours. However, further studies are necessary to investigate the mechanisms of EFV’s effects on energy expenditure. Full article

HIV-associated distal sensory polyneuropathy (HIV-DSP) remains prevalent even in the antiretroviral therapy (ART) era. Previously, we identified the upregulation of nociceptive ion channels transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) in the dorsal root ganglia (DRG) of simian immunodeficiency virus (SIV)-infected ART-treated macaques. To investigate upstream mechanisms, we performed bulk RNA-seq and pathway analysis on DRGs from uninfected, SIV-infected, and SIV-infected/ART macaques. SIV infection drove strong activation of upstream regulators of interferon γ (IFNγ) and lipopolysaccharide (LPS). Although ART reduced overall IFNγ and LPS pathway activity, the IFNγ-inducible chemokines C-X-C motif chemokine ligand (CXCL)9 and CXCL10 remained significantly upregulated. To determine whether these chemokines influence TRPV1/TRPA1 expression, we treated induced pluripotent stem cell-derived peripheral sensory neurons (iPSC-PSNs) with CXCL9 and CXCL10, which induced a significant increase in TRPV1 but not TRPA1 expression. In parallel experiments, IFNγ but not LPS stimulated monocyte-derived macrophages (MDMs) to release CXCL9 and CXCL10. Conditioned media from IFNγ-treated MDMs modestly increased TRPV1 expression in iPSC-PSNs, and pharmacological inhibition of CXCR3, the receptor of CXCL9/10, did not reduce this effect. Together, these data indicate that persistent IFNγ-driven CXCL9/10 signaling may be one contributor to nociceptor sensitization underlying HIV-DSP, even in the presence of ART. Full article

The REPRIEVE Trial recently reported high rates of sudden cardiac death (SCD) middle-aged people living with HIV-1 infection (PWH) using the WHO/NIH-recommended two nucleoside reverse transcriptase inhibitors (NRTIs)/one integrase strand inhibitor (INSTI) regimen to manage HIV-1 viremia. To date, clinically relevant animal models to delineate underlying causes for this remain limited. Here, we assessed if HIV-1-infected NOD.Cg-Prkdc^scidIl2rg^tm1Wjl/SzJ humanized mice (Hu-mice) treated with the WHO/NIH-recommended antiretroviral regimen, dolutegravir (DTG, INSTI)/tenofovir disoproxil fumarate (TDF, NRTIs)/emtricitabine (FTC, NRTIs), can recapitulate abnormalities in the ECG and subclinical structural heart disease that serve as harbingers of SCD in middle-aged PWH. HIV-1-infected and uninfected Hu-mice served as controls. After one month of infection (HIV-1_ADA), ECG intervals/segments were significantly altered. ECG changes progressively worsened as the duration of untreated infection increased. Treating HIV-1-infected animals with the DTG/TDF/FTC for eight weeks, starting four weeks after infection, prevented worsening, but did not restore ECG intervals/segments to those before infection. In hearts from DTG/TDF/FTC-treated animals, steady-state levels of the sarco-(endo) plasmic reticulum Ca²⁺ ATPase (SERCA2) were reduced by 35%. Steady-state levels of type 2 ryanodine receptor (RyR2) did not change, but its phosphorylation status at Ser2808 was 2-fold higher than that of uninfected controls, indicative of a gain-of-function. The density of perfused micro vessels and fibrosis in hearts of DTG/TDF/FTC-treated animals was not significantly different from that of HIV-1-infected and uninfected Hu-mice. These data show for the first time that HIV-1 infection is triggering abnormalities in the ECG of Hu-mice, and changes in ECG persisted with DTG/TDF/FTC treatment, independent of ischemia and/or fibrosis. They also indicate that chronic DTG/TDF/FTC treatment did not worsen ECG changes, including the QT interval. Since phosphorylation of RyR2 at Ser2808 occurs via β-adrenergic activation of protein kinase A, these new data also suggest that chronic hyperadrenergic activity may be increasing the risk of SCD via Ca²⁺ leak through RyR2. Full article

The HIV-1 envelope glycoprotein gp120 is prominently exposed on the surface of both HIV-1 virions and infected host cells, serving as a key marker of infection. gp120 plays a pivotal role in viral entry by interacting with the primary receptor, CD4, on host cells. Therapeutic strategies targeting the HIV-1 reservoir, such as anti-gp120 antibodies that trigger antibody-dependent cellular cytotoxicity (ADCC) and chimeric antigen receptor T (CAR-T) cells, rely on the presence of gp120 on the surface of infected cells to exert their effects. Consequently, accurate monitoring of gp120 expression on infected cells is essential for evaluating the pharmacological efficacy of these interventions. In this study, a sensitive, specific, and inexpensive enzyme-linked immunosorbent assay (ELISA) for quantifying HIV-1 gp120 glycoprotein was developed using a selected pair of anti-gp120 antibodies. The assay achieved a lower limit of quantitation (LLOQ) of 0.16 pM, demonstrating sensitivity comparable to that of the digital single molecule array (Simoa) platform, which exhibited a LLOQ of 0.23 pM and requires specialized instrumentation. The binding specificity of the antibodies used in the novel assay was confirmed using liquid chromatography–mass spectrometry (LC-MS), and the assay was pharmacologically validated with lysates obtained from 2D10 and MOLT IIIB cell lines. Furthermore, treatment of HIV-infected human primary CD4⁺ T cells with a targeted activator of cell kill (TACK) compound significantly reduced gp120 concentration in CD4⁺ T cell lysate compared to controls. The gp120 marker from infected cell lysates correlated with the number of gp120-positive cells detected by immunocytochemistry, as well as with HIV-1 p24 levels and cell-associated viral RNA measurements. In summary, a novel, simple, and sensitive HIV-1 gp120 ELISA has been developed and validated. This assay holds potential for investigating HIV-1 persistence and evaluating the efficacy of therapeutic agents targeting infected cells. Full article

Antiretroviral therapy (ART) effectively suppresses HIV replication but fails to eradicate latent reservoirs, leading to viral rebound after interruption. Chimeric antigen receptor (CAR) T-cell therapy offers a potential strategy to achieve durable remission. A systematic PubMed search (July 2020–June 2025) identified 253 studies on CAR-T therapy in HIV; 74 met inclusion criteria and were qualitatively analyzed. Preclinical data showed that CAR-T cells can recognize and eliminate infected cells, reach viral reservoirs, and persist long term, particularly when derived from hematopoietic stem cells. Dual-target and combination approaches with checkpoint inhibitors or latency-reversing agents enhanced antiviral efficacy. Early clinical studies confirmed safety and modest reservoir reduction. CAR-T cell therapy represents a promising step toward a functional HIV cure. Further optimization of design, integration with gene-editing technologies, and standardized clinical evaluation are required to confirm durable efficacy and safety. Full article

p17, the human immunodeficiency virus type 1 (HIV-1) matrix protein traditionally associated with viral assembly, has been recently investigated for its extracellular functions linked to vascular damage. This review examines the molecular and pathogenic signatures by which p17 and its variants (vp17s) contribute to endothelial activation, aberrant angiogenesis, and vascular inflammation, highlighting their relevance even under effective antiretroviral therapy (ART). Specifically, p17 exerts chemokine-like activities by binding to chemokine (C-X-C motif) receptor-1 and 2 (CXCR-1/2) on endothelial cells (ECs). This interaction triggers key signaling cascades, including the protein kinase B (Akt)-dependent extracellular signal-regulated kinase (ERK) pathway and endothelin-1/endothelin receptor B axis, driving EC motility, capillary formation, and lymphangiogenesis. Variants such as S75X demonstrate enhanced lymphangiogenic potency, associating them with tumorigenic processes involved in non-Hodgkin lymphoma (NHL) pathogenesis. Importantly, p17 promotes endothelial von Willebrand factor (vWF) storage and secretion, implicating a pro-coagulant state that may trigger the increased thromboembolic risks observed in HIV-positive patients. Furthermore, p17 crosses the blood–brain barrier (BBB) via CXCR-2-mediated pathways, contributing to neuroinflammation by activating microglia and astrocytes and amplifying monocyte chemoattractant protein-1 (MCP-1) levels, therefore playing a critical role in the development of HIV-associated neurocognitive disorders. Hence, the elaboration of potential therapeutic strategies finalized at inhibiting p17/vp17s’ interaction with their receptors could complement ART by addressing HIV-related neurovascular morbidity. Full article

While antiretroviral therapy (ART) has significantly improved the morbidity of HIV infection, ART may contribute to the pathogenesis of HIV associated neurocognitive impairment (HIV-NCI) by interfering with autophagic processes in astrocytes. Autophagy and mitophagy remove unwanted/damaged material and mitochondria from the intracellular environment, respectively. Dysregulated autophagy in astrocytes, abundant CNS cells with crucial homeostatic functions, contributes to many neurodegenerative diseases. Few studies have examined effects of ART on autophagy in astrocytes. We treated primary human astrocytes with a common ART regimen and performed LC3B-II and p62 turnover assays. ART significantly inhibited both LC3B-II and p62 turnover. Since p62, one autophagy receptor that mediates mitophagy, autophagic clearance of mitochondria, turnover was inhibited, we also examined mitophagy. While ART decreased BNIP3L/Nix homodimers, there were no changes in PINK1, Parkin, Mt-CO2, mitochondrial mass, or mitochondria–lysosome colocalization, indicating that ART did not inhibit mitophagy. We show that antiretroviral drugs have distinct effects on autophagic processes in astrocytes, which represents an alteration in their homeostasis, a major function of autophagy. This likely contributes to HIV-NCI. Understanding these impacts is important for improving ART for PWH, who have, by necessity, ongoing ART exposure. It also facilitates development of therapies for HIV-NCI that may include modulation of autophagy. Full article

Dendritic cells (DCs) are among the first immune cells to detect viral invasion and play a central role in initiating and shaping antiviral immune responses. Many innate and adaptive immune functions of DCs are regulated by cathepsins, proteolytic enzymes primarily found in acidic endolysosomal compartments. Different DC subsets exhibit distinct cathepsin expression patterns, influencing their functional capacities and interactions with viruses. In DCs, cathepsins contribute to virus sensing through innate receptors, regulate cytokine production and DC migration, and are essential for viral antigen degradation and loading onto MHC molecules for T-cell activation. Many viruses, however, have evolved mechanisms to alter cathepsin expression and activity, thereby subverting DC function and promoting their own persistence. Indeed, cathepsins can facilitate viral entry into DCs, promote viral replication, and support immune evasion strategies. In this review, we summarize recent advances in understanding the role of cathepsins in DC–virus interactions, emphasizing both how DCs exploit cathepsins to generate protective immune responses and how viruses manipulate cathepsin activity to their advantage. We particularly focus on clinically relevant viral pathogens, including HIV, influenza virus, hepatitis C virus, human cytomegalovirus, Ebola virus, and SARS-CoV-2, to illustrate the multifaceted influence of cathepsins on DC biology during viral infection. Full article

HIV-induced apoptosis is a contradictory complicated phenomenon that occurs at the intersection of viral persistence and host defense. HIV primarily affects CD4 T cells during an infection, causing widespread immune cell death through both direct infection and indirect (bystander) mechanisms. This immunopathologic process is caused by viral proteins such as Tat, Nef, Env, and Vpr, which modify host signaling cascades such as the PI3K/Akt, p53, NF-κB, and mitochondrial pathways. Dysregulation of pro- and anti-apoptotic mediators, particularly Bax, Bcl-2, and caspase activation, which results in mitochondrial depolarization, oxidative stress, and cytochrome c release, exacerbates immune depletion. Although apoptosis serves as a host antiviral mechanism to limit viral replication and spread, HIV exploits it to evade immune surveillance and establish chronic infection. HIV pathogenesis, which includes lymphoid tissue destruction, microbial translocation, and persistent inflammation, is significantly influenced by apoptosis of both infected and bystander cells. Furthermore, alterations in death receptor signaling (Fas/FasL and TNF pathways) and mitochondrial dysfunction highlight the delicate balance between immune defense and viral manipulation. Despite considerable progress in antiretroviral therapy, immune restoration is still incomplete due to ongoing apoptotic loss and immune exhaustion. This review examines the biological mechanisms underlying HIV-induced apoptosis, evaluates the dual role of cell death in host defense versus viral persistence, and highlights novel therapeutic targets intended to restore immune homeostasis and reduce HIV-associated immunopathology. Full article

Background/Objectives: Pregnant people with HIV (PWH) are more likely to experience systemic inflammation than pregnant people without HIV (PWoH), which may contribute to adverse outcomes in HIV-exposed uninfected (HEU) infants; however, the underlying mechanisms are not well studied. This study examined associations between maternal inflammatory markers during pregnancy and cord blood inflammatory markers and metabolomic signatures. Methods: Between 2011 and 2025, pregnant PWH and PWoH were enrolled at 24–28 weeks of gestational age. Maternal plasma was analyzed for inflammatory markers [interleukin (IL)-6, high-sensitivity C-reactive protein (hsCRP), soluble TNF-α receptor 1 (sTNFR1) and 2 (sTNFR2), soluble CD163 (sCD163), soluble CD14 (sCD14)]. At delivery, cord blood was collected for measurement of IL-6, TNF-α, IFN-γ, and IL-10 and for targeted metabolomics by ultra-performance liquid chromatography–mass spectrometry. Spearman correlation, linear regression, and weighted correlation network analysis (WGCNA) were used to evaluate associations, stratified by HIV exposure. Results: This study included 22 PWH and 47 PWoH and their infants. Among HEU infants, but not HUU infants, maternal IL-6 correlated with cord blood TNFα (r = 0.443, p < 0.05) and maternal sTNFR1 correlated with both cord blood TNFα (r = 0.617, p < 0.05) and IFNγ (r = −0.517, p < 0.05). WGCNA identified five metabolomic modules. In the HEU group, naternal sCD14 was positively associated with a metabolomic module characterized by lysophosphotidylecholines in the HEU group. Conclusions: We identified distinct patterns in the relationships between maternal inflammation and infant immune–metabolic profiles by HIV exposure status. These findings suggest that HIV infection, even with viral suppression, may alter the maternal–fetal inflammatory interface and influence early metabolic programming. Full article

Bacille Calmette-Guérin (BCG) remains the only licensed vaccine against tuberculosis (TB), administered to >100 million neonates annually. It confers approximately 70–80% protection against tuberculous meningitis and miliary TB in early childhood, under-pinning its continued use in high-burden settings. As a live-attenuated vaccine, however, BCG can rarely cause adverse reactions ranging from self-limited local lesions to life-threatening disseminated BCG disease (BCGosis), which almost exclusively occurs in infants with severe primary or acquired immunodeficiencies such as SCID, MSMD, CGD, or symptomatic HIV infection. Implementation of universal newborn screening for severe combined immunodeficiency (SCID) using the T-cell receptor excision circle (TREC) assay now enables prospective identification and deferral of these high-risk neonates, virtually eliminating fatal BCGosis. Here we synthesize global data published since 2010 on the clinical spectrum, immunopathogenesis, and epidemiology of BCG-related complications, highlighting the impact of vaccine substrain, administration technique, and host immune status on adverse-event rates. On the basis of this evidence, we propose a practical, evidence-based risk-assessment checklist (BCG-RAKE) to support safer vaccine deployment while preserving the substantial TB-control benefits of universal BCG immunization. Full article

The human immunodeficiency virus (HIV) remains a major global health challenge. A promising therapeutic strategy involves identifying human proteins capable of physically blocking viral entry by interacting with key components of the HIV attachment system. To address this challenge systematically, we developed a computational pipeline for prioritizing protein–protein interaction and applied it to identify host proteins interacting with the viral glycoprotein gp120 and cellular receptors (CD4, CCR5, CXCR4, CCR2). Our approach combined large-scale interaction modeling using AlphaFold 3 with a comprehensive comparative analysis framework. We screened a panel of 55 candidate human proteins selected through integrated bioinformatics analysis. The pipeline incorporated model confidence assessment, quantitative contact analysis, and normalization against reference interactions to generate a robust ranking of candidates. Key findings reveal several important patterns. Chemokine CCL27 uniquely demonstrated high binding potential to both CCR5 co-receptor and viral gp120, suggesting its potential for dual-blockade capability. Analysis of natural ligand interactions with chemokine receptors showed marked disparity: CC-chemokine family members exhibited significantly greater binding capacity for CCR5 and CCR2 receptors compared to CXC-family ligand interactions with CXCR4. This binding imbalance may potentially drive selective viral pressure and influence tropism evolution during disease progression. We also identified potential interactions between HIV entry components and neuropeptides including PNOC and NPY, as well as various membrane receptors beyond classical coreceptors. Furthermore, cluster analysis revealed clear separation between receptor-type and ligand-type interactors, supporting the biological plausibility of our predictions. While acknowledging limitations related to model refinement, this study provides a systematically ranked set of candidate targets for HIV therapeutic development. Beyond identifying specific HIV interaction candidates, this study establishes a generalizable computational pipeline for the prioritization of protein–protein interaction in pathogen-host systems, effectively bridging large-scale modeling. Full article

Aberrant activation of innate immunity promotes the development of pulmonary arterial hypertension (PAH); however, the role of pattern recognition by Toll-like receptors (TLRs) within the pulmonary vasculature remains unclear. To consolidate knowledge (as of June 2025) about TLRs and their interactions with viruses in PAH and to identify therapeutic implications. A narrative review of experimental and clinical studies investigating ten TLRs in the context of the pulmonary vascular microenvironment and viral infections. Activation of TLR1/2, TLR4, TLR5/6, TLR7/8, and TLR9 converges on the MyD88–NF-κB/IL-6 axis, thereby enhancing endothelial-mesenchymal transition, smooth muscle proliferation, oxidative stress, thrombosis, and maladaptive inflammation, ultimately increasing pulmonary vascular resistance. Conversely, TLR3, through TRIF–IFN-I, preserves endothelial integrity and inhibits vascular remodeling; its downregulation correlates with PAH severity, and poly (I:C) restitution has been shown to improve hemodynamics and right ventricular function. HIV-1, EBV, HCV, endogenous retrovirus K, and SARS-CoV-2 infections modulate TLR circuits, either amplifying pro-remodeling cascades or attenuating protective pathways. The “TLR rheostat” is shaped by polymorphisms, ligand biochemistry, compartmentalization, and biomechanical forces. The balance between MyD88-dependent signaling and the TRIF–IFN-I axis determines the trajectory of PAH. Prospective therapeutic strategies may include TLR3 agonists, MyD88/NF-κB inhibitors, modulation of IL-6, and combination approaches integrating antiviral therapy with targeted immunomodulation in a precision approach. Full article