Pan-caspase inhibitors induce secretion of HIV-1 latency reversal agent lymphotoxin-alpha from cytokine-primed NK cells DOI Creative Commons
Robert van Domselaar, Zamaneh Hajikhezri, Ioannis Zygouras

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 21, 2024

Abstract The persistence of HIV-1 latency reservoirs in CD4+ T cells is a significant obstacle for curing HIV-1. Shock-and-kill strategies, which aim to reactivate latent followed by cytotoxic clearance, have shown limited success in vivo due insufficient efficacy reversal agents (LRAs) and off-target effects. Natural killer (NK) cells, with their ability mediate cytotoxicity independent antigen specificity, offer promising avenue enhancing the shock-and-kill approach. Previously, we observed that pan-caspase inhibitors induce NK secrete an LRA vitro. Here, aimed identify this using targeted proteomic We identified lymphotoxin-α (LTα) as key secreted following inhibitor treatment. LTα was significantly LTR promoter activity, hallmark viral reactivation. Neutralization effectively abolished confirming its central role. Moreover, cytokine-primed but not resting human primary exhibited activity could be neutralized neutralizing antibodies. Finally, treatment did decrease kill target cells. These findings demonstrate through secretion, can treatment, without compromising cell cytotoxicity. This highlights potential enhancement strategy utilizing approaches cure research.

Language: Английский

Pan-caspase inhibitors induce secretion of HIV-1 latency reversal agent lymphotoxin-alpha from cytokine-primed NK cells DOI Creative Commons
Zamaneh Hajikhezri, Ioannis Zygouras, Anders Sönnerborg

et al.

Cell Death Discovery, Journal Year: 2025, Volume and Issue: 11(1)

Published: Feb. 4, 2025

The persistence of HIV-1 latency reservoirs in CD4+ T cells is a significant obstacle for curing HIV-1. Shock-and-kill strategies, which aim to reactivate latent followed by cytotoxic clearance, have shown limited success vivo due insufficient efficacy reversal agents (LRAs) and off-target effects. Natural killer (NK) cells, with their ability mediate cytotoxicity independent antigen specificity, offer promising avenue enhancing the shock-and-kill approach. Previously, we observed that pan-caspase inhibitors induce NK secrete an LRA vitro. Here, aimed identify this using targeted proteomic We identified lymphotoxin-α (LTα) as key secreted following inhibitor treatment. LTα was significantly LTR promoter activity, hallmark viral reactivation. Neutralization effectively abolished confirming its central role. Moreover, cytokine-primed but not resting human primary exhibited activity could be neutralized neutralizing antibodies. Finally, treatment did decrease kill target cells. These findings demonstrate through secretion, can treatment, without compromising cell cytotoxicity. This highlights potential enhancement strategy utilizing approaches cure research.

Language: Английский

Citations

1
Modelling HIV-1 control and remission DOI Creative Commons
Bharadwaj Vemparala, Shreya Chowdhury, Jérémie Guedj

et al.

npj Systems Biology and Applications, Journal Year: 2024, Volume and Issue: 10(1)

Published: Aug. 8, 2024

Remarkable advances are being made in developing interventions for eliciting long-term remission of HIV-1 infection. The success these will obviate the need lifelong antiretroviral therapy, current standard-of-care, and benefit millions living today with HIV-1. Mathematical modelling has significant contributions to efforts. It helped elucidate possible mechanistic origins natural post-treatment control, deduced potential pathways loss such quantified effects interventions, developed frameworks their rational optimization. Yet, several important questions remain, posing challenges translation promising interventions. Here, we survey recent mathematical control remission, highlight contributions, discuss avenues future developments.

Language: Английский

Citations

4
Xenon gas as a potential treatment for opioid use disorder, alcohol use disorder, and related disorders DOI Creative Commons
Marc J. Kaufman, Edward G. Meloni

Medical Gas Research, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Xenon gas is considered to be a safe anesthetic and imaging agent. Research on its other potentially beneficial effects suggests that xenon may have broad efficacy for treating health disorders. A number of reviews applications been published, but none focused substance use Accordingly, we review targets relevant the treatment disorders, with focus opioid disorder alcohol disorder. We report inhaled at subsedative concentrations inhibits conditioned memory reconsolidation withdrawal symptoms. work by others reporting antidepressant, anxiolytic, analgesic properties xenon, which could diminish negative affective states pain. discuss research supporting possibility prevent analgesic- or stress-induced tolerance and, so doing reduce risk developing The rapid kinetics, favorable safety side effect profiles, multitargeting capability suggest it used as an ambulatory on-demand rapidly attenuate maladaptive memory, physical symptoms, pain drivers disorders when they occur. also human immunodeficiency virus oncology because exploited target reservoirs, protein-induced abnormalities, cancers. Although expensive, low exert effects, separation, recovery, recycling advancements will lower costs, increasing economic feasibility therapeutic use. More needed better understand remarkable repertoire potential applications.

Language: Английский

Citations

0
Phenotyping Viral Reservoirs to Reveal HIV-1 Hiding Places DOI Creative Commons
Wenxuan Chen, Ben Berkhout, Alexander Pasternak

et al.

Current HIV/AIDS Reports, Journal Year: 2025, Volume and Issue: 22(1)

Published: Feb. 4, 2025

Abstract Purpose of Review Despite suppressive antiretroviral therapy (ART), HIV-1 reservoirs persist in various cell types and tissues reignite active replication if is stopped. Persistence the viral people with (PWH) main obstacle to achieving a cure. Identification characterization cellular tissue thus central cure research. Here, we discuss emerging insights into phenotype reservoir cells. Recent Findings persists multiple tissues, anatomic locations, types. Although contributions different CD4 + T-cell subsets are not equal, all harbor part reservoir. A number putative markers have been proposed, such as immune checkpoint molecules, integrins, pro-survival factors. CD32a expression was shown be associated very prominent enrichment DNA, although this finding has challenged. technological advances allow unbiased single-cell phenotypic analyses cells harbouring total or intact proviruses. Summary reported by several independent studies enriched on Expression some these could mechanistically linked persistence, they for instance shield from recognition promote their survival. However, so far no single marker, combination markers, can effectively distinguish HIV-infected uninfected identify

Language: Английский

Citations

0
Immune-mediated strategies to solving the HIV reservoir problem DOI
Deanna A. Kulpa, Mirko Paiardini, Guido Silvestri

et al.

Nature reviews. Immunology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 13, 2025

Language: Английский

Citations

0
Lymphoid and CXCR4 Cell Targeted Lipid Nanoparticles Facilitate HIV-1 Proviral DNA Excision DOI
Sudipta Panja,

Lubaba A. Zaman,

Chen Zhang

et al.

Published: Jan. 1, 2025

Language: Английский

Citations

0
HIV controllers: hope for a functional cure DOI Creative Commons

Zhuoya Deng,

Hongxia Yan,

Olivier Lambotte

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 25, 2025

Elite controllers (ECs) and post-treatment (PTCs) represent important models for achieving a functional cure HIV. This review synthesizes findings from immunological, genetic, virological studies to compare the mechanisms underlying HIV suppression in ECs PTCs. Although maintain viral control without antiretroviral therapy (ART), PTCs achieve following ART discontinuation. Both groups rely on adaptive innate immunity, host genetic factors, characteristics of reservoir; however, they exhibit distinct immune responses profiles. These differences provide insights into strategies sustained ART-free remission. Understanding shared unique can inform development novel therapeutic approaches, including immune-based therapies genome editing, HIV-1.

Language: Английский

Citations

0
Deep Thought on the HIV Cured Cases: Where Have We Been and What Lies Ahead? DOI Creative Commons
Qing Xiao, Sanxiu He, Chaoyu Wang

et al.

Biomolecules, Journal Year: 2025, Volume and Issue: 15(3), P. 378 - 378

Published: March 5, 2025

Antiretroviral therapy (ART) can effectively suppress the replication of human immunodeficiency virus (HIV), but it cannot completely eradicate virus. The persistent existence HIV reservoir is a major obstacle in quest for cure. To date, there have been total seven cured cases worldwide. These patients all cleared while undergoing allogeneic stem cell transplantation (allo-HSCT) hematological malignancies. However, these cases, specific mechanism by which allo-HSCT leads to eradication remains unclear, so necessary conduct an in-depth analysis. Due difficulty obtaining donors and risks associated with transplantation, this treatment method not applicable patients. There still need explore new strategies. In recent years, emerging therapies such as neutralizing antibody immunotherapy, chimeric antigen receptor T (CAR-T) therapy, gene editing, antiviral targeting attracted wide attention due their ability inhibit replication. This article first elaborates on nature reservoir, then deeply explores modalities potential success factors finally discusses current novel methods, hoping provide comprehensive feasible strategies achieving cure HIV.

Language: Английский

Citations

0
Precise CAR-T-cell Therapy Targeting Non-Cancerous Diseases: Advances in Precision Medicine and Bioengineering DOI Creative Commons
Chaojie Zhu, Fangzhou Wang, Zesheng Cheng

et al.

Precision medicine and engineering., Journal Year: 2025, Volume and Issue: unknown, P. 100024 - 100024

Published: March 1, 2025

Language: Английский

Citations

0
Heat shock protein 90 is a chaperone regulator of HIV-1 latency DOI Creative Commons

Somaya Noorsaeed,

Nawal AlBurtamani,

Ahmed Rokan

et al.

PLoS Pathogens, Journal Year: 2025, Volume and Issue: 21(4), P. e1012524 - e1012524

Published: April 1, 2025

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 hematopoietic stem cell transplantation hemizygous or homozygous ΔCCR5 donors, which broadly applicable. Alternative cure strategies include the pharmacological reactivation latently infected cells to promote their immune-mediated clearance, 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 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 that, model, mediated by T-cell receptor, phorbol esters, TNF-α, inhibition FOXO-1, agonists TLR-7 TLR-8. In cells, regulates expression induced stimulation receptor presence IL-7/IL-15 FOXO-1 inhibitor. Chemical abrogated NF-kB, NFAT AP-1 signal transduction pathways. Within population, CDRA45+ CCR7+ “naïve” CD45RA- CCR7- “effector memory” were most sensitive inhibition, did phenotype state. Our indicate can potentially strategies.

Language: Английский

Citations

0