Complex decay dynamics of HIV virions, intact and defective proviruses, and 2LTR circles following initiation of antiretroviral therapy

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(6)

Published: Feb. 2, 2022

Significance In persons living with HIV-1 who start antiretroviral therapy, virus in the blood decreases rapidly to below detection limit. The decrease occurs two phases: a rapid initial first weeks, followed by second, slower phase occurring over next few months. These decay processes are important because infected cells that remain may become part of stable latent reservoir prevents cure. levels presumably reflects loss cells, but relationship between free and has been unclear. Here, we have analyzed this question using an assay distinguishes intact defective forms viral genome.

Language: Английский

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The cell biology of HIV-1 latency and rebound

Retrovirology, Journal Year: 2024, Volume and Issue: 21(1)

Published: April 5, 2024

Abstract Transcriptionally latent forms of replication-competent proviruses, present primarily in a small subset memory CD4 + T cells, pose the primary barrier to cure for HIV-1 infection because they are source viral rebound that almost inevitably follows interruption antiretroviral therapy. Over last 30 years, many factors essential initiating transcription have been identified studies performed using transformed cell lines, such as Jurkat T-cell model. However, highlighted this review, several poorly understood mechanisms still need be elucidated, including molecular basis promoter-proximal pausing transcribing complex and detailed mechanism delivery P-TEFb from 7SK snRNP. Furthermore, central paradox remains unsolved: how initial rounds achieved absence Tat? A critical limitation models is do not recapitulate transitions between active effector cells quiescent cells. Therefore, investigation latency reversal LRA efficacy proper physiological context requires utilization models. Recent mechanistic latently infected recovered donors ex vivo cellular demonstrated blocks restrictive epigenetic features at proviral promoter, cytoplasmic sequestration key initiation NFAT NF-κB, vanishingly low expression elongation factor P-TEFb. One foremost schemes eliminate residual reservoir deliberately reactivate proviruses enable clearance persisting cells—the “Shock Kill” strategy. For become efficient, effective, non-toxic latency-reversing agents (LRAs) must discovered. Since multiple restrictions limit reactivation understanding signaling stimulating biogenesis, activation, reversing prerequisite development more effective LRAs.

Language: Английский

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In Vivo Dynamics of the Latent Reservoir for HIV-1: New Insights and Implications for Cure

Annual Review of Pathology Mechanisms of Disease, Journal Year: 2021, Volume and Issue: 17(1), P. 271 - 294

Published: Nov. 5, 2021

Although antiretroviral therapy (ART) can reduce viremia to below the limit of detection and allow persons living with HIV-1 (PLWH) lead relatively normal lives, rebounds when treatment is interrupted. Rebound reflects viral persistence in a stable latent reservoir resting CD4+ T cells. This now recognized as major barrier cure focus intense international research efforts. Strategies infection include interventions eliminate this reservoir, prevent rebound from or enhance immune responses such that replication effectively controlled. Here we consider recent developments understanding composition how it be measured clinical studies. We also discuss exciting new insights into vivo dynamics reasons for its remarkable stability. Finally discoveries on complex processes govern rebound.

Language: Английский

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HIV-induced membraneless organelles orchestrate post-nuclear entry steps

Journal of Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 14(11)

Published: Oct. 31, 2022

ABSTRACT HIV integration occurs in chromatin sites that favor the release of high levels viral progeny; alternatively, virus is also able to discreetly coexist with host. The infection perturbs cellular environment inducing remodelling nuclear landscape. Indeed, HIV-1 triggers clustering host factor CPSF6, but underlying mechanism poorly understood. Our data indicate usurps a recently discovered biological phenomenon, called liquid–liquid phase separation, hijack cell. We observed CPSF6 clusters as part HIV-induced membraneless organelles (HIV-1 MLOs) macrophages, one main target cell types. describe MLOs follow phase-separation rules and represent functional biomolecular condensates. highlight hubs reverse transcription, while double-stranded DNA, once formed, rapidly migrates outside these structures. Transcription-competent proviruses localize near LEDGF-abundant regions, known be active sites. Therefore, orchestrate events prior step create favorable for replication. This study uncovers single host–viral complexes their landscape, which markedly restructured by HIV-1.

Language: Английский

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Mcl-1 Protein and Viral Infections: A Narrative Review

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(2), P. 1138 - 1138

Published: Jan. 17, 2024

MCL-1 is the prosurvival member of Bcl-2 family. It prevents induction mitochondria-dependent apoptosis. The molecular mechanisms dictating host cell viability gain importance in context viral infections. premature apoptosis infected cells could interrupt pathogen replication cycle. On other hand, death following effective assembly progeny particles may facilitate virus dissemination. Thus, various viruses can interfere with regulation network to their advantage. Research has shown that infections affect intracellular amount modify apoptotic potential cells, fitting it “schedule” A growing body evidence suggests virus-dependent deregulation level contribute several virus-driven diseases. In this work, we have described role caused by viruses. We also presented a list promising antiviral agents targeting protein. discussed results indicate targeted interventions addressing anti-apoptotic MCL1 as new therapeutic strategy for cancers well investigation cellular and involved engaging better understanding survival balance.

Language: Английский

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HIV Latency in Myeloid Cells: Challenges for a Cure

Pathogens, Journal Year: 2022, Volume and Issue: 11(6), P. 611 - 611

Published: May 24, 2022

The use of antiretroviral therapy (ART) for Human Immunodeficiency Virus (HIV) treatment has been highly successful in controlling plasma viremia to undetectable levels. However, a complete cure HIV is hindered by the presence replication-competent HIV, integrated host genome, that can persist long term resting state called viral latency. Resting memory CD4+ T cells are considered biggest reservoir persistent infection and often studied exclusively as main target an cure. other cell types, such circulating monocytes tissue-resident macrophages, harbor integrated, HIV. To develop focus needed not only on compartment, but also these myeloid reservoirs infection. In this review, we summarize their importance when designing strategies challenges associated identification specific targeting “shock kill” approach.

Language: Английский

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Oral Cannabidiol Treatment Is Associated with an Anti-Inflammatory Gene Expression Signature in Myeloid Cells of People Living with HIV

Cannabis and Cannabinoid Research, Journal Year: 2024, Volume and Issue: 9(4), P. 1028 - 1037

Published: Jan. 22, 2024

Introduction: HIV-related comorbidities appear to be related chronic inflammation, a condition characterizing people living with HIV (PLWH). Prior work indicates that cannabidiol (CBD) might reduce inflammation; however, the genetics underpinning of this effect are not well investigated. Our main objective is detect gene expression alterations in human peripheral blood mononuclear cells (PBMCs) from PLWH after at least 1 month CBD treatment. Materials and Methods: We analyzed ∼41,000 PBMCs three baseline treatment (27–60 days) through single-cell RNA sequencing. Results: obtained coherent signature, characterized by an anti-inflammatory activity, differentially expressed genes myeloid cells. Conclusions: study shows how associated Clinical Trial Registration: NCT05209867.

Language: Английский

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Latency Reversing Agents and the Road to a HIV Cure

Pathogens, Journal Year: 2025, Volume and Issue: 14(3), P. 232 - 232

Published: Feb. 27, 2025

HIV-1 infection cannot be cured due to the presence of latently infected cells. These cells do not produce virus, but they can resume virus production at any time in absence antiretroviral therapy. Therefore, people living with HIV (PLWH) need take lifelong Strategies have been coined eradicate viral reservoir by reactivating and subsequently killing them. Various latency reversing agents (LRAs) that reactivate vitro ex vivo identified. The most potent LRAs also strongly activate T therefore applied vivo. Many general cell activation identified tested clinical trials. Although some could reduce size trials, so far, failed reservoir. More recently, immune modulators PLWH, first results seem indicate these may possibly improve immunological control after therapy interruption. Potentially, combinations size, future, enable PLWH live without developing HIV-related disease

Language: Английский

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Bid Protein: A Participant in the Apoptotic Network with Roles in Viral Infections

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(6), P. 2385 - 2385

Published: March 7, 2025

The BH3-interacting domain death agonist (Bid), a proapoptotic signaling molecule of the B-cell lymphoma 2 (Bcl-2) family, is key regulator mitochondrial outer membrane (MOM) permeability. Uniquely positioned at intersection extrinsic and intrinsic apoptosis pathways, Bid links receptor to mitochondria-dependent cascade can also be activated by endoplasmic reticulum (ER) stress. In its active forms, cleaved (cBid) truncated (tBid), it disrupts MOM integrity via Bax/Bak-dependent independent mechanisms. Apoptosis plays dual role in viral infections, either promoting or counteracting propagation. Consequently, viruses modulate favor their replication. deregulation activity contributes oncogenic transformation, inflammation, immunosuppression, neurotoxicity, pathogen propagation during various infections. this work, we explore Bid’s structure, function, activation processes, targeting. We describe induction involvement infections with multiple viruses. Additionally, discuss therapeutic potential antiviral strategies. Understanding pathways offers valuable insights into host–virus interactions pathogenesis This knowledge may facilitate development novel approaches combat virus-associated diseases effectively.

Language: Английский

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

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

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