Genetic Variants in the NOD-like Receptor Signaling Pathway Are Associated with HIV-1/AIDS in a Northern Chinese Population

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(8), P. 3484 - 3484

Published: April 8, 2025

The NOD-like receptor (NLR) signaling pathway may influence human immunodeficiency virus (HIV) clearance and CD4+ T cell recovery through inflammatory responses, but its specific mechanism requires further investigation. A deeper understanding of genetic variations can provide new insights into the biological mechanisms underlying occurrence development syndrome (AIDS). By utilizing multiple bioinformatic analyses functional annotations, we identified single-nucleotide polymorphisms (SNPs) in NLR that affect HIV-1 infection AIDS progression. Then, a case–control study was performed to screen risk-related variants by genotyping candidate SNPs sample 500 men who have sex with (MSM) healthy controls from Han population Northern China. results revealed significant association between five (NLRP3 rs4612666, MAVS rs17857295, rs6084497, rs16989000, JAK1 rs4244165) infection. Interestingly, gene–gene interaction model composed exhibited cumulative effect on disease. Specially, increase risk alleles carried samples elevated contracting HIV-1. In addition, three (IL1B rs1143623, STAT1 rs1467199 rs2066804) were associated counts patients AIDS. Three (OAS1 rs1131454, NLRP3 rs10754558, rs867335) found be related clinical staging This finding provides genes progression among MSM

Language: Английский

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The HIV-1 Transcriptional Program: From Initiation to Elongation Control

Journal of Molecular Biology, Journal Year: 2024, Volume and Issue: unknown, P. 168690 - 168690

Published: June 1, 2024

A large body of work in the last four decades has revealed key pillars HIV-1 transcription control at initiation and elongation steps. Here, I provide a recount this collective knowledge starting with genomic elements (DNA nascent TAR RNA stem-loop) factors (cellular viral transactivator Tat), later transitioning to assembly regulation complexes, role chromatin structure. Compelling evidence support core transcriptional program regulated by sequential concerted action cellular Tat promote sustain elongation, highlighting efficiency small virus take over its host produce high levels required for replication. summarize new advances including use CRISPR-Cas9, genetic tools acute factor depletion, imaging study dynamics, bursting progression through multiple phases cycle. Finally, describe current challenges future major discuss areas that deserve more attention both bolster our basic open up therapeutic opportunities.

Language: Английский

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Immune Characteristics and Immunotherapy of HIV-Associated Lymphoma

Current Issues in Molecular Biology, Journal Year: 2024, Volume and Issue: 46(9), P. 9984 - 9997

Published: Sept. 10, 2024

In the era of antiretroviral therapy (ART), mortality among people living with human immunodeficiency virus (HIV) has significantly decreased, yet population HIV remains substantial. Among (PLWH), HIV-associated lymphoma (HAL) surpassed Kaposi's sarcoma to become most common tumor in this developed countries. However, there a dearth comprehensive and systematic understanding regarding lymphomas. This review aims shed light on changes immune system PLWH characteristics microenvironment lymphoma, specific focus system's role these individuals. Additionally, it seeks explore recent advancements immunotherapy for treatment intending enhance strategies population.

Language: Английский

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Interventions during Early Infection: Opening a Window for an HIV Cure?

Viruses, Journal Year: 2024, Volume and Issue: 16(10), P. 1588 - 1588

Published: Oct. 9, 2024

Although combination antiretroviral therapy (ART) has been a landmark achievement for the treatment of human immunodeficiency virus (HIV), an HIV cure remained elusive. Elimination latent reservoirs that persist throughout infection is most challenging barrier to cure. The progressive marked by increasing size and diversity until effective immune response mobilized, which can control but not eliminate infection. stalemate between replication manifested establishment viral set point. ART initiation during early stage limits reservoir development, preserves function, improves quality life, may lead ART-free remission in few people living with (PLWH). However, overwhelming majority PLWH, alone does HIV, lifelong needed sustain suppression. A critical area research focused on determining whether could be functionally cured if additional treatments are provided alongside ART. Several interventions including Block Lock, Shock Kill, broadly neutralizing antibody (bNAb) therapy, adoptive CD8+ T cell gene have demonstrated delayed rebound and/or animal models some PLWH. Whether or their application improve success less studied. Herein, we review current state clinical investigative discuss potential likelihood post-treatment initiated

Language: Английский

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Adeno-Associated Virus (AAV)-Delivered Exosomal TAT and BiTE Molecule CD4-αCD3 Facilitate the Elimination of CD4 T Cells Harboring Latent HIV-1

Microorganisms, Journal Year: 2024, Volume and Issue: 12(8), P. 1707 - 1707

Published: Aug. 18, 2024

Combinatorial antiretroviral therapy (cART) has transformed HIV infection from a death sentence to controllable chronic disease, but cannot eliminate the virus. Latent HIV-1 reservoirs are major obstacles cure infection. Previously, we engineered exosomal Tat (Exo-Tat) reactivate latent reservoir of resting CD4+ T cells. Here, present an eradication platform, which uses our previously described Exo-Tat activate virus cells guided by specific binding domain CD4 in interleukin 16 (IL16), attached N-terminus exosome surface protein lysosome-associated membrane 2 variant B (Lamp2B). Cells with gp120 expressed on cell membranes then targeted for immune cytolysis BiTE molecule CD4-αCD3, colocalizes and CD3 cytotoxic lymphocytes. Using primary blood obtained treated individuals, find that this combined approach led significant reduction replication-competent infected clonal vitro system. Furthermore, adeno-associated serotype DJ (AAV-DJ) was used deliver Exo-Tat, IL16lamp2b CD4-αCD3 genes constructing them one AAV-DJ vector (the plasmid named pEliminator). The coculture patients Huh-7 AAV-Eliminator viruses clearance experiment, could have implications reducing viral vivo, indicating Eliminator AAV potential be developed into therapeutic biologics

Language: Английский

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HIV-1 reservoir landscape of post-treatment control

Current Opinion in HIV and AIDS, Journal Year: 2024, Volume and Issue: 20(1), P. 99 - 108

Published: Oct. 21, 2024

Purpose of review This explores the viral reservoir landscape in individuals who control replication after treatment interruption (TI), designated as post-treatment controllers (PTCs). Identifying their virologic features is crucial to inform drug-free HIV remission strategies. Recent findings Traditionally characterized small, likely due early treatment, PTCs, TI, exhibits limited transcriptional activity, residual and subsequent proviral diversity. Intact proviruses are found be restricted. In nonhuman primate this depletion intact already observed lymph nodes before suggesting that mechanisms begin during antiretroviral therapy. Furthermore, recent studies suggest immune-driven deep latency associated with repressive epigenetic integration sites PTCs. While molecular mapping virological PTCs increasingly precise coupled in-depth immunologic assays, robust predictive biomarkers still lacking. Summary Despite sample sizes heterogeneous definitions, common include restricted size fewer latency. Ongoing research using innovative technologies will further elucidate underlying control, paving way for successful cure interventions.

Language: Английский

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Heat shock protein 90 is a master regulator of HIV-1 latency

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 23, 2024

An estimated 32 million people live with HIV-1 globally. Combined antiretroviral therapy suppresses viral replication but interruption results in rebound from a latent reservoir mainly found memory CD4+ T cells. Treatment is therefore lifelong and not curative. Eradication of this requires heterologous DCCR5 hematopoietic stem cell transplantation, which broadly applicable. Alternative cure strategies include the pharmacological reactivation latently infected cells to promote their immune-mediated clearance, or induction deep latency. latency multifactorial linked activation status cell. Hence perturb latency, multiple pathways need be simultaneously targeted without affecting function. Hsp90 has been shown regulate although knowledge on limited. Because hsp90 promotes proper folding numerous cellular proteins required for gene expression, we hypothesized that might master regulator We tested hypothesis using polyclonal Jurkat model ex-vivo primary mediated by T-cell receptor, phorbol esters, TNF-a, inhibition FOXO-1, agonists TLR-7 TLR-8. Inhibition abrogated NF-kB, NFAT AP-1 signal transduction pathways, phenotype was recapitulated targeting TAK1, an client protein. Within population, naive effector were most sensitive inhibition, did state. Our indicate can potentially strategies.

Language: Английский

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Conjugation of anti-HIV gp41 monoclonal antibody to a drug capable of targeting resting lymphocytes produces an effective cytotoxic anti-HIV immunoconjugate

Journal of Virology, Journal Year: 2024, Volume and Issue: 98(10)

Published: Sept. 16, 2024

ABSTRACT HIV-infected cells persisting in the face of suppressive antiretroviral therapy are barrier to curing infection. Cytotoxic immunoconjugates targeted HIV antigens on cell surface may clear these cells. We showed efficacy mouse and macaque models using immunotoxins, but immunogenicity blunted effect. As an alternative, we propose antibody drug conjugates (ADCs), as used cancer immunotherapy. In cancer, target is a dividing cell, whereas it not be HIV. screened cytotoxic drugs human primary lines. An anthracycline derivative, PNU-159682 (PNU), was highly both proliferating resting Human anti-gp41 mAb 7B2 conjugated ricin A chain or PNU. The were tested vitro for anti-viral effect, vivo tolerability. specificity killing demonstrated Env+ Env− toxin conjugate more potent killed rapidly, 7B2–PNU effective at levels achievable patients. well tolerated mice; toxic when administered intraperitoneally intravenously. have produced ADC with potential persistent reservoir non-dividing while avoiding immunogenicity. anti-HIV greatest utility part “activate purge” regimen, involving viral activation reservoir. This unique comparison immunotoxin by same systems. IMPORTANCE infection can controlled anti-retroviral therapy, cannot cured. Despite years that suppresses HIV, patients again become viremic shortly after discontinuing treatment. long-lived population memory T retain genes encoding secrete infectious no longer suppressed therapy. therapies described here use antibodies poisons kill this These several types, including protein toxins (immunotoxins) anti-cancer (antibody conjugates, ADCs). previously shown had therapeutic effects animal models, elicited anti-drug immune response. Here, prepared ADC, which would less likely provoke response, show its eliminating

Language: Английский

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The EZH2 inhibitor tazemetostat mitigates HIV immune evasion, reduces reservoir formation, and promotes durable CD8+ T-cell revitalization

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 15, 2024

Abstract Persistent HIV reservoirs in CD4⁺ T-cells pose a barrier to curing infection. We identified overexpression of enhancer zeste homolog 2 (EZH2) HIV-infected T- cells that survive cytotoxic T lymphocyte (CTL) exposure, suggesting mechanism CTL resistance. Inhibition EZH2 with the FDA-approved drug tazemetostat increased surface expression major histocompatibility complex class I (MHC-I) on T-cells, counterbalancing Nef–mediated MHC-I downregulation. This improved CTL-mediated elimination and suppressed viral replication vitro. In participant-derived xenograft mouse model, elevated pro-apoptotic protein BIM facilitating CD8⁺ T-cell–mediated reductions reservoir seeding. Additionally, promoted sustained skewing toward less differentiated exhausted phenotypes. Our findings reveal as novel resistance support clinical evaluation enhance clearance improve CD8+ T-cell function.

Language: Английский

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The 3rd anniversary of Frontiers in Virology: aiming to consolidate the virus research

Frontiers in Virology, Journal Year: 2024, Volume and Issue: 4

Published: Oct. 25, 2024

mutability and its wild-bird origin. Experts are really anxious about other terrible influenzapandemics by new type viruses. About 40 years ago, we also encountered another dreadful readily mutable virus HIV-1 that causes AIDS. Since the AIDS outbreak began, approximately 100 million people have been infected with died of AIDS/AIDSrelated diseases. still stays pandemic functional cure is not yet achieved (4-7). Thus, causative needs to be studied in more detail precisely understand viral persistent state humans. Toward this direction, further medical investigation as well fundamental basic research should performed (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). retroviral genome integrates into those humans establish inseparable virus-host relationship, firm solid virological understanding intracellular events particularly required address follow significant numbers pre-clinical clinical issues on And now, witnessing global pandemics caused corona pox viruses (SARS-CoV-2 Mpox virus, respectively) (19)(20)(21)(22)(23)(24)(25)(26)(27)(28). As a matter course, basis previous profound knowledge various viruses, extensive efforts paid biology/molecular biology two valid preventive therapeutic measures. One problem here high adaptability despite their quite low mutation rates (19,28). This observation can explained some specific mechanisms such recombinational mutations (the non-processive replicase-driven template switching mechanism for SARS-CoV-2) (19,29) transient gene duplications accordion model virus) (28,30). In any case, deal mutant appearing course infection.As described above, IFV, HIV-1, SARS-CoV-2, highly adaptable restrictive hostile environments. These dexterous being able ingeniously modify them significantly response variously changing circumstances. Through genomic adaptive and/or own proteins, circumvent barriers cellular anti-viral factors, host natural/acquired immunity against antivirals, vaccines. an example escape than mutations, innately encodes accessory proteins allow it evade restriction factors (31)(32)(33)(34). Collectively, likely frequently change environment-dependent way. So far, know entity concerned only nucleotide sequencings. means running behind just retrospectively following Most virologists including our group adopted strategy due limitations laboratory virology, whereas many biologically results accumulated exploring Our team has investigated adaptation process clarify significance synonymous substitutions structure-function relationship combining experimental virology data/computational science, successfully published obtained series articles (35)(36)(37)(38)(39)(40)(41)(42). On one hand, different from approaches, class studies based big data massive scope scale attracted attention unprecedented concept past decade (43)(44)(45)(46)(47)(48)(49)(50)(51)(52). The characterized methods collect analyze large sets, NSG, CRISPR-based technologies, machine learning, algorithms. targets were: epidemiology disease, plant ecology, evolution, drug-resistance, databases research, computational tools. sciences may aid forecasting future virus-related issues. Big approaches surely synergize consolidate predictive role modern virology."Frontiers Virology" continues platform cutting edge virology. It covers all subjects indicated names specialty sections. Furthermore, "Frontiers appreciates leading-edge technology virusrelated matters. ideal goal prospectively foresee everything effects hosts/environments, beforehand conclusion, earnestly hope submission your important papers scientific value.

Language: Английский

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