Search Results (165)

Background/Objectives: During the repair of a wounded epithelium, keratinocytes become invasive via the epithelial-to-mesenchymal transition (EMT) process. Usually temporary and controlled, EMT persists in a chronically inflamed epithelium and is exacerbated in epithelial dysplasia and dysregulated in invasive carcinomas. Here we investigated the effects that IL-1 beta, IL-6, and IL-8, inflammatory cytokines expressed in specimens from OPMDs and OSCCs, have on NOKs and OSCC cells. Methods: AKT activation and EMT induction were assessed along with cellular invasiveness. Results: IL-1 beta, IL-6, and IL-8 induced EMT in NOKs, ex novo conferring them invasive capacity. The same cytokines exacerbated the constitutive EMT and invasiveness of OSCC cells. Since these phenomena were accompanied by AKT activation, we tested whether they could be influenced by RTV, a long-used anti-HIV drug that was previously found to block the activation of human AKT and exert antitumor effects. We observed that therapeutic amounts of RTV counteract all the above-mentioned tumorigenic activities of ILs. Finally, consistent with the key role that AKT and EMT play in OSCC radio-resistance, RTV increased OSCC cells’ sensitivity to therapeutic doses of ionizing radiation. Conclusions: These preliminary in vitro findings encourage the use of RTV to prevent the malignant evolution of OPMDs, reduce the risk of OSCC metastasis, and improve the outcomes of anti-OSCC radiotherapy. Full article

RNA viruses pose significant threats to global health, causing diseases such as COVID-19, HIV/AIDS, influenza, and dengue. These viruses are characterized by high mutation rates, rapid evolution, and the ability to evade traditional antiviral therapies, making effective treatment and prevention particularly challenging. In recent years, CRISPR/Cas13 has emerged as a promising antiviral tool due to its ability to specifically target and degrade viral RNA. Unlike conventional antiviral strategies, Cas13 functions at the RNA level, providing a broad-spectrum and programmable approach to combating RNA viruses. Its flexibility allows for rapid adaptation of guide RNAs to counteract emerging viral variants, making it particularly suitable for highly diverse viruses such as SARS-CoV-2 and HIV. This review discusses up-to-date applications of Cas13 in targeting a wide range of RNA viruses, including SARS-CoV-2, HIV, dengue, influenza, and other RNA viruses, focusing on its therapeutic potential. Preclinical studies have demonstrated Cas13’s efficacy in degrading viral RNA and inhibiting replication, with applications spanning prophylactic interventions to post-infection treatments. However, challenges such as collateral cleavage, inefficient delivery, potential immunogenicity, and the development of an appropriate ethical framework must be addressed before clinical translation. Future research should focus on optimizing crRNA design, improving delivery systems, and conducting rigorous preclinical evaluations to enhance specificity, safety, and therapeutic efficacy. With continued advancements, Cas13 holds great promise as a revolutionary antiviral strategy, offering novel solutions to combat some of the world’s most persistent viral threats. Full article

Background/Objective: Fentanyl plays a pivotal role in the opioid epidemic, defined by four waves of overdose deaths. To analyse fentanyl research trends, examining its links to mental health, pharmaceutical development, healthcare, diseases, and pathophysiology within the broader social and health context of the time. Methods: To understand the evolution of scientific publications on fentanyl and its relationship to the opioid crisis, a search using Web of Science Core Collection and PubMed was conducted. A total of 53,670 documents were retrieved related to opioid scientific production, among which 1423 articles (3%) focused specifically on fentanyl. The 21,546 MeSH terms identified in these documents were analysed by publication year and specific fields: Psychiatry and Psychology, Chemicals and Drugs, Healthcare, Diseases, and Phenomena and Processes. R-statistical/FactoMineR libraries were used for the correspondence analysis. Results: In the first overdose death wave, research focused on improving therapies and reducing side effects. The second wave emphasised detoxification methods with naltrexone, methadone, and behavioural therapies. The third wave addressed psychological treatments and HIV-syringe-sharing prevention. The fourth wave prioritised less addictive analogues and understanding consumer profiles to combat the epidemic. Conclusions: Fentanyl research has evolved alongside real-world challenges, reinforcing the connection between patients’ needs, healthcare professionals’ roles, illicit users, policymakers, and the research community’s contributions to addressing both therapeutic use and its broader societal impact. These findings highlight the necessity for an interdisciplinary approach to scientific research integrating prevention, treatment, education, legal reform, and social support, emphasising the need for public health policies and collaborative research to mitigate its impact. Full article

HIV-1 Tat acts as a central molecular switch governing the transition between viral latency and active replication, making it a pivotal target for HIV-1 functional cure strategies. By binding to the viral long terminal repeat (LTR) and hijacking host transcriptional machinery, Tat dynamically regulates RNA polymerase II processivity to alter viral transcription states. Recent studies reveal its context-dependent variability: while Tat recruits chromatin modifiers and scaffolds non-coding RNAs to stabilize epigenetic silencing in latently infected cells, it also triggers rapid transcriptional amplification upon cellular activation. This review systematically analyzes the bistable regulatory mechanism of Tat and investigates advanced technologies for reprogramming this switch to eliminateviral reservoirs and achieve functional cures. Conventional approaches targeting Tat are limited by compensatory viral evolution and poor bioavailability. Next-generation interventions will employ precision-engineered tools, such as AI-optimized small molecules blocking Tat-P-TEFb interfaces and CRISPR-dCas9/Tat chimeric systems, for locus-specific LTR silencing or reactivation (“block and lock” or “shock and kill”). Advanced delivery platforms, including brain-penetrant lipid nanoparticles (LNPs), enable the targeted delivery of Tat-editing mRNA or base editors to microglial reservoirs. Single-cell multiomics elucidates Tat-mediated clonal heterogeneity, identifying “switchable” subpopulations for timed interventions. By integrating systems-level Tat interactomics, epigenetic engineering, and spatiotemporally controlled delivery, this review proposes a roadmap to disrupt HIV-1 persistence by hijacking the Tat switch, ultimately bridging mechanistic insights to clinical applications. Full article

Background: Human immunodeficiency virus (HIV) remains a global health challenge despite significant advancements in antiretroviral therapy and prevention strategies. Developing a safe and effective vaccine that protects people worldwide has been a major goal, yet the genetic variability and rapid mutation rate of the virus continue to pose substantial challenges. Methods: In this review paper, we aim to provide a comprehensive review of previous vaccine candidates and the progress made in HIV vaccine clinical trials, spanning from the late 1990s to 2025. PubMed and ClinicalTrials.gov were searched for English-language Phase 1–3 HIV vaccine trials published from 1990 to March 2025. After de-duplication, titles/abstracts and then full texts were screened; trial phase, regimen, immunogenicity, efficacy, and correlates were extracted into a structured spreadsheet. Owing to platform heterogeneity, findings were synthesized narratively and arranged chronologically to trace the evolution of vaccine strategies. Results: Early vaccine trials demonstrated that a protein subunit vaccine failed to protect against infection, revealing the complexity of HIV evasion strategies and shifting the focus to a comprehensive immune response, including both antibody and T-cell responses. Trials evaluating the role of viral vectors in generating cell-mediated immunity were also insufficient, and suggested that targeting T cell response alone was not enough. In 2009, the RV144 trial made a breakthrough by showing partial protection against HIV infection and providing the first indication of efficacy. This partial success influenced subsequent trials, prompting researchers to further explore the complex immune response required for protection and consider combinations of vaccine technologies to achieve robust, long-lasting immunity. Conclusion: Despite setbacks, decades of rigorous efforts have provided significant contributions to HIV vaccine discovery and development, offering hope for preventing and protecting against HIV infection. The field remains active by continuing to advance our understanding of the virus, refining vaccine strategies, and employing novel technologies. Full article

We investigated HIV-1 immune evasion mechanisms in a slow progressor (CBJC515) by constructing pseudoviruses expressing autologous Env proteins. Intriguingly, all pseudoviruses exhibited resistance to the broadly neutralizing antibody (bNAb) PGT135. Using site-directed mutagenesis and chimeric Env construction, we identified distinct escape mechanisms: early 2005 strains lost the N332 glycan site, while 2006/2008 strains retained key epitopes but developed resistance through structural modifications in the V1/V4/C2 regions or acquired novel N-glycosylation sites (N398/N611). These findings provide insights into how HIV-1 can escape from N332-directed bNAb responses without altering the epitope itself. Furthermore, chimeric experiments also elucidated regional co-evolution and functional maintenance: the V1V2 region broadly interfered with envelope protein function, while the V3 region may exhibit compensatory activity, restoring functionality and mitigating deleterious polymorphisms in other regions to keep Env antigenic diversity. These results offer valuable mechanistic clues that may inform the development of next-generation HIV-1 vaccines. Full article

Over the past several decades, viral vector-based vaccines have emerged as some of the most versatile and potent platforms in modern vaccinology. Their capacity to deliver genetic material encoding target antigens directly into host cells enables strong cellular and humoral immune responses, often superior to what traditional inactivated or subunit vaccines can achieve. This has accelerated their application to a wide array of pathogens and disease targets, from well-established threats like HIV and malaria to emerging infections such as Ebola, Zika, and SARS-CoV-2. The COVID-19 pandemic further highlighted the agility of viral vector platforms, with several adenovirus-based vaccines quickly authorized and deployed on a global scale. Despite these advances, significant challenges remain. One major hurdle is pre-existing immunity against commonly used vector backbones, which can blunt vaccine immunogenicity. Rare but serious adverse events, including vector-associated inflammatory responses and conditions like vaccine-induced immune thrombotic thrombocytopenia (VITT), have raised important safety considerations. Additionally, scaling up manufacturing, ensuring consistency in large-scale production, meeting rigorous regulatory standards, and maintaining equitable global access to these vaccines present profound logistical and ethical dilemmas. In response to these challenges, the field is evolving rapidly. Sophisticated engineering strategies, such as integrase-defective lentiviral vectors, insect-specific flaviviruses, chimeric capsids to evade neutralizing antibodies, and plug-and-play self-amplifying RNA approaches, seek to bolster safety, enhance immunogenicity, circumvent pre-existing immunity, and streamline production. Lessons learned from the COVID-19 pandemic and prior outbreaks are guiding the development of platform-based approaches designed for rapid deployment during future public health emergencies. This review provides an exhaustive, in-depth examination of the historical evolution, immunobiological principles, current platforms, manufacturing complexities, regulatory frameworks, known safety issues, and future directions for viral vector-based vaccines. Full article

Cryptococcal meningitis remains a leading cause of morbidity and mortality among individuals with HIV/AIDS, particularly in resource-limited settings. Treatment begins with induction therapy followed by consolidation and maintenance. Evidence related to induction therapy has evolved significantly over the past decade. Current treatment relies primarily on three antifungal agents: amphotericin B, flucytosine, and fluconazole, each with distinct mechanisms of action and limitations. The World Health Organization’s 2022 guidelines for induction therapy recommend a single high dose of liposomal amphotericin B combined with 14 days of flucytosine and fluconazole. The 2010 IDSA guidelines for induction therapy recommend amphotericin B deoxycholate and flucytosine for two weeks. The U.S. CDC/NIH/IDSA/HIVMA joint guidelines and the ECCM/ISHAM/ASM joint guidelines list both options, but the recommendation varies by setting resources (e.g., resource-limited vs. other). The newer treatment approaches (single high-dose liposomal amphotericin B) that are supported by trials such as AMBITION-cryptococcal meningitis have limited adoption in high-resource settings, with recent studies showing that only 14% of North American infectious disease providers have utilized the regimen. Adjunctive medications, such as dexamethasone, tamoxifen, and sertraline, have proven ineffective or harmful in clinical trials. This review underscores the ongoing challenges in cryptococcal meningitis treatment and the need for continued research to improve patient outcomes, tracing the evolution from past monotherapy approaches to current combination strategies while exploring future directions. Full article

Non-Hodgkin lymphoma (NHL) remains the most common malignancy and cause of death among human immunodeficiency virus (HIV-1)-positive individuals, its prevalence remaining even after the introduction of combined antiretroviral therapy (cART). The mechanisms underlying B-cell tumorigenesis are still poorly understood; however, recently, a key role for p17 variants (vp17s) in lymphoma development has been clearly elucidated. Here, we describe findings on lymphomagenic vp17s and discuss their potential role as diagnostic and prognostic markers that could be used to predict the HIV-positive patients at higher risk of developing lymphoma. Specifically, vp17s endowed with amino acid (aa) insertions in their C-terminal region, at positions 114–115 (Glu-Lys), 117–118 (Ala–Ala) and 125–126 (Gly–Asp), were found to be significantly more prevalent in HIV-positive individuals with lymphoma as compared to those without. Alterations in the primary aa sequences destabilize the protein, exposing a previously hidden functional epitope which interacts with protease-activated receptor-1 (PAR-1) and stimulates the protein kinase B pathway, conferring oncogenic potential to vp17s and possibly contributing to lymphomagenesis. Therefore, ultradeep sequencing technologies, such as next-generation sequencing, could serve as a valuable screening tool for identifying and monitoring the HIV-positive patients at higher risk of developing lymphoma, paving the way for targeted preventive intervention strategies. Full article

Histoplasmosis has traditionally been described as having discrete geographic areas of endemicity. Over the last few decades, it has become more and more clear that these areas are not accurate depictions of where histoplasmosis can occur. Our understanding of where histoplasmosis occurs has improved in recent years due to improving access to diagnostic testing and increased reporting as well as larger at-risk populations (HIV and non-HIV immune suppression) resulting in more cases. Although areas of relatively higher risk and case numbers certainly still exist, histoplasmosis has been observed in much of the world at this point. Our knowledge of the geographic distribution of histoplasmosis, though improving, remains incomplete. While diagnostic testing has traditionally been confined to visualization and/or culture in much of the world, antigen testing has emerged as an excellent tool. Unfortunately access to antigen testing has been inadequate for much of the world, but this has started to change in recent years and will likely change more dramatically in the near future, assuming ongoing positive developments in the area of lateral flow tests for antigen testing. In this review, we describe the current understanding of the geographic distribution of histoplasmosis, the current landscape of diagnostic testing, and the evolution of both areas with an eye towards the future. Full article

The evolutionary origin of the variants of concern (VOCs) of SARS-CoV-2, characterized by a large number of new substitutions and strong changes in virulence and transmission rate, is intensely debated. The leading explanation in the literature is a chronic infection in immunocompromised individuals, where the virus evolves before returning into the main population. The present article reviews less-investigated hypotheses of VOC emergence with transmission between acutely infected hosts, with a focus on the mathematical models of stochastic evolution that have proved to be useful for other viruses, such as HIV and influenza virus. The central message is that understanding the acting factors of VOC evolution requires the framework of stochastic multi-locus evolution models, and that alternative hypotheses can be effectively verified by fitting results of computer simulation to empirical data. Full article

Introduction: Focal segmental glomerulosclerosis (FSGS) is a pattern of kidney injury with diverse causes and pathogeneses, resulting in podocyte injury and depletion. It can be classified as primary, genetic, or secondary. Because FSGS classically has a worse prognosis in patients with nephrotic syndrome, most studies have focused on the treatment and evolution of these patients, resulting in a lack of data related to patients without nephrotic syndrome. The objective of this study was to establish the main etiologies, characteristics, and evolution of renal disease in FSGS patients with nephrotic and non-nephrotic proteinuria. Methods: This was a retrospective, single-center study that included 140 patients with a biopsy-confirmed diagnosis of FSGS in the 2009–2017 period. Patients were separated into those with and those without nephrotic syndrome at diagnosis, and these two groups were compared in terms of the clinical characteristics, histological profile, and outcome. Non-nephrotic patients with unfavorable progression were selected for ultrastructural analysis with electron microscopy. Results: During the study period, 32.9% of the patients with FSGS had non-nephrotic proteinuria at diagnosis. This group had a larger proportion of patients with hypertension and a not otherwise specified FSGS variant on histology. The proportion of patients with secondary forms of FSGS was comparable between the two groups, with HIV infection and systemic lupus erythematosus being predominant. Progression to renal replacement therapy occurred in 31.3% of the patients in the nephrotic group and in 26.8% of those in the non-nephrotic group, with no statistical difference between them. All of the non-nephrotic group patients who progressed to renal replacement therapy were analyzed by electron microscopy, the diagnosis of FSGS was confirmed, and there was the finding of high chronicity in these patients. Conclusions: Among patients with FSGS, those without nephrotic syndrome had a poor renal outcome at a frequency similar to that of those with nephrotic syndrome. Factors related to better renal survival were having had a complete response to treatment in the case of those with nephrotic syndrome and having achieved proteinuria values of less than 1.5 g/day in the case of those without nephrotic syndrome. Full article

The HIV (Human Immunodeficiency Virus) epidemic remains a significant public health issue, requiring ongoing access to preventive methods. This study aimed to analyze the evolution of the HIV epidemic in Lower Silesia from 2010 to 2020, focusing on the key populations. A retrospective analysis of the medical records from newly diagnosed HIV patients at a major HIV clinic in Wroclaw was conducted, examining demographic data, infection routes, and laboratory results. An 84% increase in newly diagnosed HIV cases was observed over the decade, with the most common route of infection being sex between men (70% among those with a known infection route). These patients were generally in better clinical condition compared to their heterosexual counterparts, as indicated by a higher median CD4+ T cell count (465/μL vs. 250/μL). The changes in clinical status and infection routes were statistically significant. The HIV epidemic in Lower Silesia has shifted, with a notable rise in new infections among men who have sex with men. Heterosexual patients were often diagnosed at more advanced stages. Prevention strategies should adapt to these changing trends, with education and testing accessibility remaining priorities nationwide. Full article

The effects of immunodeficiency associated with chronic HIV infection on COVID-19 disease and viral persistence have not been directly addressed in a controlled setting. In this pilot study, we exposed two pigtail macaques (PTMs) chronically infected with SIVmac239, exhibiting from very low to no CD4 T cells across all compartments, to SARS-CoV-2. We monitored the disease progression, viral replication, and evolution, and compared these outcomes with SIV-naïve PTMs infected with SARS-CoV-2. No overt signs of COVID-19 disease were observed in either animal, and the SARS-CoV-2 viral kinetics and evolution in the SIVmac239 PTMs were indistinguishable from those in the SIV-naïve PTMs in all sampled mucosal sites. However, the single-cell RNA sequencing of bronchoalveolar lavage cells revealed an infiltration of functionally inert monocytes after SARS-CoV-2 infection. Critically, neither of the SIV-infected PTMs mounted detectable anti-SARS-CoV-2 T-cell responses nor anti-SARS-CoV-2 binding or neutralizing antibodies. Thus, HIV-induced immunodeficiency alone may not be sufficient to drive the emergence of novel viral variants but may remove the ability of infected individuals to mount adaptive immune responses against SARS-CoV-2. Full article

We recently demonstrated that Simian–HIV (SHIV)-infected neonate rhesus macaques (RMs) generated heterologous HIV-1 neutralizing antibodies (NAbs) with broadly-NAb (bNAb) characteristics at a higher frequency compared with their corresponding dam. Here, we characterized genetic diversity in Env sequences from four neonate or adult/dam RM pairs: in two pairs, neonate and dam RMs made heterologous HIV-1 NAbs; in one pair, neither the neonate nor the dam made heterologous HIV-1 NAbs; and in another pair, only the neonate made heterologous HIV-1 NAbs. Phylogenetic and sequence diversity analyses of longitudinal Envs revealed that a higher genetic diversity, within the host and away from the infecting SHIV strain, was correlated with heterologous HIV-1 NAb development. We identified 22 Env variable sites, of which 9 were associated with heterologous HIV-1 NAb development; 3/9 sites had mutations previously linked to HIV-1 Env bNAb development. These data suggested that viral diversity drives heterologous HIV-1 NAb development, and the faster accumulation of viral diversity in neonate RMs may be a potential mechanism underlying bNAb induction in pediatric populations. Moreover, these data may inform candidate Env immunogens to guide precursor B cells to bNAb status via vaccination by the Env-based selection of bNAb lineage members with the appropriate mutations associated with neutralization breadth. Full article