Search Results (229)

The block-and-lock strategy aims to achieve a functional cure for human immunodeficiency virus type 1 (HIV-1) infection by enforcing durable, drug-independent silencing of proviral transcription. Several latency-promoting agents have been described that effectively limit viral reactivation in vitro or in animal models. However, most approaches induce only partial or reversible transcriptional repression and have not yet been translated into safe and effective clinical interventions. This review summarizes the molecular mechanisms underlying block-and-lock strategies and critically evaluates the limitations of current candidate compounds. We highlight recent advances in understanding HIV-1 integration site selection, focusing on the roles of lens epithelium-derived growth factor p75 (LEDGF/p75) and cleavage and polyadenylation specificity factor subunit 6 (CPSF6) in directing proviral integration toward gene-dense, transcriptionally active chromatin. Pharmacological disruption of the LEDGF/p75–integrase interaction by LEDGF/p75 inhibitors (LEDGINs) redirects proviral integration toward less transcriptionally active genomic regions that are more resistant to reactivation. Recent tandem knockout experiments, however, demonstrate that CPSF6 plays a dominant role in guiding HIV-1 integration toward gene-dense, transcriptionally active chromatin. LEDGIN treatment has been linked to the preferential targeting of proviruses to heterochromatin-rich regions within the nuclear interior. By contrast, CPSF6 knockout redirects integration toward peripheral heterochromatin, especially lamina-associated domains (LADs), genomic regions typically exhibiting stronger and more stable transcriptional repression than interior heterochromatin. These findings suggest that therapeutic modulation of CPSF6 may exert a more profound and durable effect on proviral silencing within a block-and-lock framework. Nevertheless, complete CPSF6 ablation is associated with severe cellular toxicity. The challenges associated with CPSF6-related adverse effects and potential strategies to overcome these limitations are discussed. Full article

Despite effective antiretroviral therapy, HIV persists in diverse tissue reservoirs that pose major barriers to a cure. This review examines the heterogeneous maintenance mechanisms of HIV reservoirs in lymph nodes, intestinal mucosa, and the central nervous system (CNS). It analyzes how distinct tissue microenvironments—including immune-privileged niches, specialized cellular subsets, and local signaling networks—govern viral persistence and latency. Lymph nodes function as a dynamic hub interconnected with systemic reservoirs; the intestinal mucosa represents a site shaped by barrier integrity, microbial translocation, and mucosal immunity; the CNS constitutes a compartmentalized sanctuary protected by the blood–brain barrier. The review further discusses tissue-specific antiretroviral drug penetration and targeted clearance strategies, providing a foundation for developing multi-site intervention approaches toward HIV cure. Full article

Despite the remarkable success of antiretroviral therapy (ART) in suppressing human immunodeficiency virus type 1 (HIV-1) replication, viral persistence remains a major barrier to cure. This persistence is sustained by heterogeneous cellular reservoirs in which viral expression is tightly regulated by host-dependent molecular mechanisms. Beyond the canonical cluster of differentiation 4 (CD4+) T-cell reservoirs, HIV-1 establishes long-lived infection in myeloid cells, glial populations within the central nervous system (CNS), and additional non-canonical cellular niches, each characterized by distinct transcriptional, epigenetic, and immune environments. In this review, we synthesize recent advances in understanding how HIV-1 expression, latency, and reactivation are shaped across diverse susceptible cell types. We highlight cell-type-specific mechanisms governing viral integration, chromatin organization, transcriptional elongation, innate immune sensing, host restriction factors, and cytoskeletal regulation. Particular emphasis is placed on how host signaling pathways and immune microenvironments contribute to reservoir stability and heterogeneity, complicating eradication strategies. We further discuss immunomodulatory approaches that seek to modulate viral expression without exacerbating immune activation. By integrating molecular, cellular, and immunological perspectives, this review provides a framework for understanding HIV-1 persistence as a context-dependent process and underscores the need for cell-type-tailored strategies in HIV cure research. Full article

Despite viral suppression with antiretroviral therapy (ART), reservoirs of Human Immunodeficiency Virus (HIV) persist in anatomical compartments throughout the body, including the brain. We have previously demonstrated that the HIV long terminal repeats (LTRs) isolated from the brains of non-virally suppressed people with HIV (PWH) are phylogenetically and functionally distinct from those isolated from matched peripheral tissue. While intact, transcriptionally competent HIV genomes persist within the brains of virally suppressed PWH, whether HIV LTRs are intact, functional, and compartmentalized relative to the periphery, as in non-virally suppressed PWH, remains unclear. HIV LTRs were extracted from frontal cortex post-mortem brain and matched peripheral tissues of virally suppressed PWH (n = 5). Following single-genome amplification, sequences were phylogenetically analyzed and transcriptional activity was assessed. In contrast to non-virally suppressed PWH, LTR sequences failed to compartmentalize between the brain and peripheral compartments. Identical LTR sequences were observed across brain and peripheral tissues in 2/5 PWH. While the LTRs remain transcriptionally active, mutations, insertions and deletions predicted to reduce transcription factor binding affinity at key binding sites, including C/EBP, NF-κB, and Sp1 sites, were observed and found to result in reduced basal transcriptional activity. The role of these mutations in latency and viral persistence remains unclear. Full article

HIV latency, driven by a complex interplay of host factors, remains a key barrier to viral clearance. Current latency-reversing agents (LRAs) demonstrate limited efficacy and specificity, and none have been approved for clinical use. Although natural products have shown promise as LRAs, the therapeutic potential of fungal metabolites remains underexplored. Candida albicans, a prevalent human commensal and opportunistic pathogen, produces diverse secondary metabolites that can influence host pathways, affecting latency dynamics. This study aimed to investigate the latency-modulating potential of secondary metabolites of C. albicans using an integrative network pharmacology and computational pipeline. C. albicans secondary metabolites were retrieved from the literature, screened for drug-likeness, and mapped to human targets and biological pathways annotated in HIV latency. Key metabolites, hub genes, and pathways were systematically characterized through network and computational analyses. Six drug-like candidates, identified from 185 absorption, distribution, metabolism, excretion, and toxicity (ADMET)-screened metabolites, collectively mapped to 369 human genes with a 6.5% overlap in HIV latency (176 shared and 20 hub genes). These overlapping genes were significantly enriched for signal transduction, membrane localization, and adaptive responses to chemical stimuli. Kyoto encyclopedia of genes and genomes (KEGG) enrichment revealed oncogenic diseases (non-small cell lung, pancreatic, and prostate cancers) and latency-associated cascades, including PD-L1/PD-1, HIF-1, Ras, PI3K-Akt, calcium, and cAMP signaling. Six hub targets (MAPK1, PIK3CA, MAPK3, EGFR, MTOR, and AKT1) were consistently annotated within the top 30 KEGG pathways and displayed strong binding affinities for MET 15 and MET 119. Molecular dynamics (MD) simulations confirmed favorable binding free energies (BFEs) and stable conformational dynamics for the top-ranked metabolite MET 15. C. albicans secondary metabolites preferentially target oncogenic signaling networks central to HIV latency maintenance, notably PI3K/AKT/MTOR and MAPK/ERK, which regulate cell survival, metabolic homeostasis, and viral transcriptional repression. MET 15 is a top-ranked candidate metabolite for HIV latency-reversing therapeutics and warrants experimental validation in established latency models. Full article

Human immunodeficiency virus type 1 (HIV-1) is a retrovirus that integrates into the host cell’s DNA as a provirus. Transcription from the provirus is regulated in large part by cellular proteins and epigenetic factors. These may be repressive or permissive to productive infection. The host factors that regulate this balance are therefore attractive targets for HIV-1 therapeutics. Indeed, proviral chromatin is the focus of two of the current HIV-1 cure strategies. “Shock and Kill” uses latency reversal agents to open the provirus’s chromatin, promoting high levels of gene expression that induce the killing of infected cells. “Block and Lock” uses latency promoting agents to induce heterochromatin, blocking transcription and forcing HIV-1 into a state of deep latency. Here, the compounds investigated in both strategies are reviewed, including their chemical structures, mechanisms of action, and clinical results. Finally, the use of CRISPR-Cas therapeutics and the impact of chromatin architecture on its efficacy are discussed. Full article

Persistent HIV reservoirs in long-lived macrophages pose a unique and formidable challenge to achieving HIV cure. HIV-infected macrophages are more resistant than CD4+ T cells to both virus- and immune-mediated death pathways including apoptosis, facilitating their persistence in tissue sanctuary sites and potential to contribute to viral rebound upon therapy cessation. This resistance is driven by HIV-induced modulation of both intrinsic and extrinsic apoptotic pathways, alongside survival mechanisms including autophagy. In this review, we examine the biological mechanisms promoting macrophage survival and explore novel translational strategies aimed at subverting this resistance. Crucially, we highlight the methodological limitations hindering progress, including the scarcity of robust in vitro macrophage models, the influence of culture conditions, and physiological relevance to macrophages in vivo. We emphasise that a macrophage-inclusive approach, incorporating improved pre-clinical models and developing clinical measurements to quantify the reservoir in human tissue, is essential to successfully eliminate this distinct reservoir and advance toward sustained ART-free remission. Full article

The persistence of latent HIV-1 reservoirs in individuals on antiretroviral therapy (ART) remains a major barrier to cure, necessitating strategies such as “shock and kill” using latency-reversing agents (LRAs). However, current LRAs show limited clinical efficacy, highlighting the need for novel interventions. This study evaluated the in vitro latency-reversing potential of Product Nkabinde (PN) and Gnidia sericocephala using J-Lat A2 (subtype B) and J-Lat C clones T66 and T17 (subtype C) cells. Cell viability was assessed using flow cytometry with Live/Dead dye. Reactivation potential was further tested in combination with established LRAs: panobinostat, SAHA, and TNF-α. G. sericocephala induced dose-dependent latency reversal, with 26.1% of J-Lat A2 and 15.8% of J-Lat T66 cells GFP-positive at 106 µg/mL (p = 0.0001). Co-treatment with LRAs enhanced reactivation—34.6% with SAHA and 87.2% with TNF-α in J-Lat A2 cells, and 56.9% with SAHA and 65.4% with TNF-α in J-Lat T66 cells (p = 0.0001)—while maintaining cell viability above 90%. PN showed minimal activity (≤1.3% GFP-positive) and no effect in combination assays. Fractional inhibitory concentration index analysis revealed no synergistic interactions. Ex vivo, PN and G. sericocephala induced limited increases in HIV-1 gag RNA without substantial cytotoxicity. These findings demonstrate that G. sericocephala effectively reverses HIV-1 latency and potentiates TNF-α-induced reactivation, supporting its potential as a plant-derived LRA for future “shock and kill” HIV-1 cure strategies. Full article

Kaposi’s Sarcoma-associated herpesvirus (KSHV) and Epstein–Barr virus (EBV) are oncogenic gammaherpesviruses with high prevalence in sub-Saharan Africa. Both viruses are typically acquired during childhood, establishing lifelong latency. While viral reactivation into the lytic cycle has been mainly studied in adult HIV-infected populations—and more recently in the context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) co-infection—the dynamics of KSHV and EBV infection in children remain poorly understood. Here, we characterize pediatric patients (n = 175; median age 4.6 years; IQR 2.0–8.3) presenting with inflammatory conditions during the COVID-19 pandemic in South Africa (from July 2020 to February 2024). Including a healthy, non-inflammatory control group, we found widespread exposure to SARS-CoV-2 (70.9% seropositivity), with 72.6% of the children being seropositive for EBV and 19.4% for KSHV. There were no significant differences in seroprevalence between children with inflammatory conditions and healthy controls for any of these viruses, although SARS-CoV-2 antibody titers were significantly higher in the inflammatory group, while EBV immune responses were lower in children presenting with inflammation. Among the KSHV-seropositive children, no active viremia was detected (as determined by the absence of viral DNA in the peripheral blood). In contrast, 34.4% of EBV-seropositive children had detectable EBV viral load, with a modestly higher proportion in the inflammatory group. However, EBV viral load levels were comparable between children diagnosed with Multisystem Inflammatory Syndrome in Children (MIS-C), Kawasaki Disease (KD), and other inflammatory conditions. Logistic regression analyses revealed that increasing age was significantly associated with higher risk of SARS-CoV-2 and EBV seropositivity, but not KSHV. Notably, the risk of EBV DNA detection in the peripheral blood decreased with age. In summary, this study suggests effective immunological control of gammaherpesvirus infections in HIV-negative paediatric patients, even in the presence of inflammatory conditions that might otherwise trigger viral reactivation. Full article

Epstein–Barr virus (EBV) is a key oncogenic pathogen implicated in the development of lymphomas, particularly among HIV-positive and immunocompromised individuals. While the association between EBV and lymphoma is well established, the mechanisms underlying progression from infection to malignancy—especially in the head and neck region—remain incompletely understood. This review offers a comprehensive analysis of the pathophysiological pathways by which EBV and HIV contribute to lymphomagenesis, with an emphasis on latency patterns, immune evasion, and epigenetic “hit and run” oncogenesis. Notably, it integrates novel findings on the diagnostic implications of EBV latency proteins, explores HIV-mediated B-cell dysregulation, and evaluates the emerging landscape of targeted therapies, including monoclonal antibodies and lytic cycle inducers. By focusing specifically on head and neck lymphomas, this review underscores a clinically underrepresented domain and offers insights that may guide future diagnostics, surveillance, and treatment strategies in vulnerable patient populations. This review also highlights the pressing need for improved animal models and continued research into EBV-specific therapeutic targets. Full article

People living with HIV-1 (PLWH) are part of the so-called “fragile” populations to which COVID-19 vaccines were/are strongly recommended. The fact that most widely used COVID-19 vaccines rely on the production of a biologically active SARS-CoV-2 Spike protein expressed by synthetic mRNA poses the relevant question of whether and how this vaccination influences the fate of the HIV-1 reservoir. This report presents a detailed analysis of the literature data on the effects of SARS-CoV-2 Spike and COVID-19 vaccines on HIV-1 latently infected cells. Despite being limited in number, the experimental evidences consistently indicate that vaccine mRNA and/or SARS-CoV-2 Spike can effectively reactivate latent HIV-1. This conclusion has been drawn after “in vitro”, “ex vivo”, and “in vivo” assays, and with virus-associated Spike, soluble Spike, or its intracellular expression, as well as with COVID-19 mRNA vaccines. On the other hand, real-world observations on vaccinated PLWH under antiretroviral therapy (ART) provided evidence of HIV-1 reactivation almost exclusively in PLWH with unsuppressed viremia, as measured in terms of size of the HIV-1 reservoir. Although several issues still need to be clarified through urgent additional investigations, these data suggest the possibility that the Spike protein and/or the vaccine mRNA molecules affect the HIV-1 latency in PLWH. Full article

HTLV-1 and HIV-1 represent biologically significant, structurally close, and equally problematic yet divergent human retroviruses. Although both infect CD4+ T cells and share similar structural elements, they differ markedly in genomic stability, transmission dynamics, clinical progression, and, most importantly, their transcriptional regulatory mechanisms. HTLV-1, an ancient virus with a limited global burden, often remains asymptomatic for decades before potentially causing ATL or HAM/TSP. Conversely, HIV-1, a relatively recent zoonotic transmission, undergoes rapid replication, exhibits high genetic diversity, and causes progressive immunodeficiency unless controlled by antiretroviral therapy (ART). At the molecular level, HTLV-1 maintains proviral latency through a balanced bidirectional transcription of regulatory genes (e.g., Tax and HBZ) that manipulate host transcription and immune evasion pathways, facilitating persistence and oncogenesis. HBZ and Tax were shown to contribute to driving the progressive acquisition of Treg-like and HLA class II phenotype in chronically activated CD4+ T-cells, promoting tolerogenic antigen presentation and immune evasion in ATL cells. This well-controlled differential expression of HTLV-1 regulatory genes is attributed to multiple intragenic virus regulatory mechanisms, which will be discussed in this review. In contrast, HIV-1 transcription is driven by a tightly regulated 5′ LTR promoter involving host factors such as NF-κB, Sp1, AP-1, and NFAT, among others, with strong influence imposed by the landscape of the provirus integration site, playing a pivotal role in latency and reactivation. The distinct regulatory circuitry of each virus suggests a key difference in their essential regulation, with HTLV-1 primarily relying on intragenic mechanisms, while HIV-1 relies more heavily on interactions with the surrounding host environment to control its expression. This difference underscores unique therapeutic challenges in managing viral latency, persistence, and pathogenesis. Full article

Dendritic cells (DCs) are essential for antiviral immunity but are also susceptible to HIV-1 infection. Although sensing and restriction pathways in DCs are well described, the mechanisms underlying latent infection and its functional consequences remain unclear. In this study, we performed transcriptomic profiling of monocyte-derived DCs harboring transcriptionally active (Active-HIV) or latent HIV-1 (Latent-HIV) proviruses using a dual-reporter virus. Gene set enrichment analysis revealed suppression of metabolic and stress-modulatory programs in Active-HIV compared to unexposed DCs. In contrast, Latent-HIV showed broad downregulation of pathways, including interferon and innate responses and metabolic programs, indicating a hyporesponsive and dampened antiviral state despite the absence of differentially expressed genes (DEGs). DEG analysis of Active-HIV versus Latent-HIV showed that active transcription associates with cellular stress, cytoskeletal remodeling, and RNA processing. Functional analyses further demonstrated the activation of RNA processes, the suppression of antigen-presentation pathways, and altered membrane and cytoskeletal signaling in Active-HIV. These pathways suggest that transcriptionally active HIV-1 is linked to cellular programs supporting replication, coinciding with a metabolically strained yet immunologically engaged state that may impair antigen presentation. Conversely, latently infected DCs display a hyporesponsive state consistent with proviral silencing. This dichotomy reveals distinct mechanisms of DC dysfunction that may facilitate HIV-1 persistence and immune evasion. Full article

Herpes simplex viruses (HSV-1 and HSV-2) are highly prevalent human pathogens that establish lifelong latency in sensory neurons, posing a persistent challenge to global public health. Their clinical manifestations range from mild, self-limiting orolabial lesions to severe, life-threatening conditions such as disseminated neonatal infections, focal encephalitis, and herpetic stromal keratitis, which can lead to irreversible corneal blindness. Beyond direct pathology, HSV-mediated genital ulcerative disease (GUD) significantly enhances mucosal susceptibility to HIV-1 and other sexually transmitted infections, amplifying co-infection risk and disease burden. Despite decades of clinical reliance on nucleoside analogues such as acyclovir, the therapeutic landscape has stagnated with rising antiviral resistance, toxicity associated with prolonged use, and the complete inability of current drugs to eliminate latency or prevent reactivation continue to undermine effective disease control. These persistent gaps underscore an urgent need for next-generation antivirals that operate through fundamentally new mechanisms. Marine ecosystems, the planet’s most chemically diverse environments, are providing an expanding repertoire of antiviral compounds with significant therapeutic promise. Recent discoveries reveal that marine-derived polysaccharides, sulfated glycans, peptides, alkaloids, and microbial metabolites exhibit remarkably potent and multi-targeted anti-HSV activities, disrupting viral attachment, fusion, replication, and egress, while also reshaping host antiviral immunity. Together, these agents showcase mechanisms and scaffolds entirely distinct from existing therapeutics. This review integrates emerging evidence on structural diversity, mechanistic breadth, and translational promise of marine natural products with anti-HSV activity. Collectively, these advances position marine-derived compounds as powerful, untapped scaffolds capable of reshaping the future of HSV therapeutics. 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