Monocyte to macrophage differentiation and changes in cellular redox homeostasis promote cell type-specific HIV latency reactivation

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(19)

Опубликована: Апрель 29, 2024

HIV latency regulation in monocytes and macrophages can vary according to signals directing differentiation, polarization, function. To investigate these processes, we generated an model THP-1 showed differential levels of reactivation among clonal populations. Monocyte-to-macrophage differentiation HIV-infected primary human CD14+ cells induced that virus production increased concomitant with macrophage differentiation. We applied the monocyte-to-macrophage (MLat) assess biological mechanisms regulating dynamics during pinpointed protein kinase C signaling pathway activation Cyclin T1 upregulation as inherent regulate reactivation. Macrophage polarization regulated latency, revealing proinflammatory M1 suppressed while anti-inflammatory M2 promoted Because rely on reactive-oxygen species (ROS) exert numerous cellular functions, disrupted redox pathways found inhibitors thioredoxin (Trx) system acted latency-promoting agents T-cells monocytes, but opposingly latency-reversing macrophages. explored this mechanism Auranofin, a clinical candidate for reducing reservoirs, demonstrated Trx reductase inhibition led ROS NF-κB activity, which macrophages, not monocytes. Collectively, cell type-specific differences could pose barrier eradication strategies.

Язык: Английский

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A critical assessment of male HIV/AIDS patients’ satisfaction with antiretroviral therapy and its implications for sustainable development in Sub-Saharan Africa

Journal of Health Organization and Management, Год журнала: 2025, Номер unknown

Опубликована: Янв. 31, 2025

Purpose The emergence of unique and destructive viruses, such as COVID-19, has claimed lives, disrupted health systems diverted resources from addressing the needs male HIV/AIDS patients in context antiretroviral therapy other HIV/AIDS-related issues. This study aims to assess patients’ satisfaction with its implications for sustainable development Sub-Saharan Africa. Design/methodology/approach Satisfaction, word-of-mouth, trust revisit intention were variables research model. A quantitative method was utilized. Data collected 400 who received medical attention hospitals Gombe State, Nigeria, utilizing convenience sampling method. SmartPLS used data analysis. Findings results show that a positive impact on trust, word-of-mouth intention. Furthermore, had significant intentions. Word-of-mouth played mediating role relationship between Trust an insignificant Additionally, effect Healthcare organisations should prioritise patient because it influences their likelihood returning. Addressing HIV can significantly enhance overall healthcare experience, which would lead them spread word mouth. Research limitations/implications administrators make top priority provide superior services match or exceed expectations. focused gender. Also, empirical is carried out public hospitals; however, there are some differences types terms factors affect revisits. We employed cross-sectional study. As result, we recommend expanding into longitudinal study, allows researcher validate causal mechanism obtain more generalizable. Practical managers actively encourage reviews recommendations. Setting up record distribute success stories improve hospital’s reputation attract new patients. Increased advertising naturally result encouraging encounters outcomes. establish channels sharing information regarding therapies, procedures support transparent easy obtain. Patients’ intentions return follow-up appointments be favourably influenced by education value ongoing care. Social Male satisfied care have tendency professionals more, promotes enhanced therapeutic outcomes greater compliance treatment regimens. Positive comments those condition also reduce stigma motivate community members seek treatment, fostering supportive environment living HIV/AIDS. emphasises how important providers stronger, empathy connections, could contribute decreasing disparities. Originality/value investigates highlights WOM mediate this relationship.

Язык: Английский

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Depicting HIV-1 Transcriptional Mechanisms: A Summary of What We Know

Viruses, Год журнала: 2020, Номер 12(12), С. 1385 - 1385

Опубликована: Дек. 3, 2020

Despite the introduction of combinatory antiretroviral therapy (cART), HIV-1 infection cannot be cured and is still one major health issues worldwide. Indeed, as soon cART interrupted, a rapid rebound viremia observed. The establishment viral latency persistence virus in cellular reservoirs constitute main barrier to HIV eradication. For this reason, new therapeutic approaches have emerged purge or restrain order cure infected patients. However, multifactorial process that depends on various mechanisms. Since these therapies mainly target transcription, their development requires detailed precise understanding regulatory mechanism underlying transcription. In review, we discuss complex molecular transcriptional network regulating gene expression by focusing involvement host cell factors could used potential drug targets design strategies and, larger extent, reach an functional cure.

Язык: Английский

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The Block-and-Lock Strategy for Human Immunodeficiency Virus Cure: Lessons Learned from Didehydro–Cortistatin A

The Journal of Infectious Diseases, Год журнала: 2020, Номер 223(Supplement_1), С. S46 - S53

Опубликована: Окт. 23, 2020

Antiretroviral therapy effectively controls human immunodeficiency virus (HIV) infection. However, a reservoir of latently infected cells persists under suppressive therapy, constituting major barrier to an HIV cure. The block-and-lock approach functional cure aims at the transcriptional and epigenetic silencing proviruses, blocking viral reactivation in absence preventing disease progression transmission, despite presence detectable integrated proviruses. This has been put forward for exploration based on activity didehydro-cortistatin A, inhibitor activator Tat. Here we review mechanisms by which A inhibition Tat's feedback loop amplification results promoter, discuss benefits limitations

Язык: Английский

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Why the HIV Reservoir Never Runs Dry: Clonal Expansion and the Characteristics of HIV-Infected Cells Challenge Strategies to Cure and Control HIV Infection

Viruses, Год журнала: 2021, Номер 13(12), С. 2512 - 2512

Опубликована: Дек. 14, 2021

Antiretroviral therapy (ART) effectively reduces cycles of viral replication but does not target proviral populations in cells that persist for prolonged periods and can undergo clonal expansion. Consequently, chronic human immunodeficiency virus (HIV) infection is sustained during ART by a reservoir long-lived latently infected their progeny. This landscape undergoes change over time on ART. One the forces driving expansion CD4 T cells, which presents key obstacle to HIV eradication. Potential mechanisms include general immune activation, antigenic stimulation, homeostatic proliferation, provirus-driven expansion, each likely contributes varying, largely unmeasured, amounts maintaining reservoir. The role clinical events, such as infections or neoplasms, these remains uncertain, characterizing may shed light approaches eradicate HIV. A limited number individuals have been cured setting bone marrow transplant; information from other studies identify means control without In this review, we describe HIV-1 persistence along with attempts modify factors part reduction cure strategies.

Язык: Английский

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Defective HIV-1 genomes and their potential impact on HIV pathogenesis

Retrovirology, Год журнала: 2022, Номер 19(1)

Опубликована: Июнь 28, 2022

Defective HIV-1 proviruses represent a population of viral genomes that are selected for by immune pressures, and clonally expanded to dominate the persistent proviral genome landscape. There examples RNA protein expression from these compromised which generated variety mechanisms. Despite evidence transcribed translated, their role in HIV pathogenesis has not been fully explored. The potential participate stimulation is particularly relevant considering accumulation cells harboring defective over course antiretroviral therapy people living with HIV. different tissues could drive innate sensing mechanisms inflammation. They may also alter antiviral T cell responses myeloid functions directly contribute associated chronic comorbidities. Understanding impact needs be considered as we advance cure strategies focus on targeting diverse genomes.

Язык: Английский

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Breaking the Silence: Regulation of HIV Transcription and Latency on the Road to a Cure

Viruses, Год журнала: 2023, Номер 15(12), С. 2435 - 2435

Опубликована: Дек. 15, 2023

Antiretroviral therapy (ART) has brought the HIV/AIDS epidemic under control, but a curative strategy for viral eradication is still needed. The cessation of ART results in rapid rebound from latently infected CD4+ T cells, showing that control replication alone does not fully restore immune function, nor it eradicate reservoirs. With better understanding factors and mechanisms promote latency, current approaches are primarily focused on permanent silencing cells ("block lock") or reactivating HIV-1 gene expression combination with restoration strategies to eliminate HIV host ("shock kill"). In this review, we provide summary current, most promising cure strategies, including an analysis both latency-promoting agents (LPA) latency-reversing (LRA) have shown promise vitro, ex vivo, human clinical trials reduce reservoir.

Язык: Английский

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HIV-Associated Neurocognitive Disorder: A Look into Cellular and Molecular Pathology

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(9), С. 4697 - 4697

Опубликована: Апрель 25, 2024

Despite combined antiretroviral therapy (cART) limiting HIV replication to undetectable levels in the blood, people living with continue experience HIV-associated neurocognitive disorder (HAND). HAND is associated impairment, including motor and memory loss. has been detected brain within 8 days of estimated exposure mechanisms for this early entry are being actively studied. Once having entered into central nervous system (CNS), degrades blood-brain barrier through production its gp120 Tat proteins. These proteins directly toxic endothelial cells neurons, propagate inflammatory cytokines by activation immune dysregulation tight junction The BBB breakdown progression disease. One main hurdles treatment latent pool cells, which insensitive cART prolong inflammation harboring provirus long-lived that can reactivate, causing damage. Multiple strategies studied combat HAND; however, clinically, these approaches have insufficient require further revisions. goal paper aggregate known challenges HAND.

Язык: Английский

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Key Players in HIV-1 Transcriptional Regulation: Targets for a Functional Cure

Viruses, Год журнала: 2020, Номер 12(5), С. 529 - 529

Опубликована: Май 11, 2020

HIV-1 establishes a life-long infection when proviral DNA integrates into the host genome. The provirus can then either actively transcribe RNA or enter latent state, without viral production. switch between these two states is governed in great part by protein, Tat, which promotes transcript elongation. Latency also influenced availability of transcription factors, integration site, and surrounding chromatin environment. reservoir established first few days serves as source rebound upon treatment interruption. Despite effective suppression replication antiretroviral therapy (ART), to below detection limit, ART ineffective at reducing size. Elimination this has become major goal cure field. However, aside from ideal total eradication genome, an remission functional probably more realistic. “block-and-lock” approach aims transcriptional silencing reservoir, render suppressed promoters extremely difficult reactivate latency. There are unfortunately no clinically available specific inhibitors. Understanding mechanisms that regulate latency expected provide novel targets be explored approaches.

Язык: Английский

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The question of the question: impactful implementation science to address the HIV epidemic

Journal of the International AIDS Society, Год журнала: 2022, Номер 25(4)

Опубликована: Апрель 1, 2022

Questions about the implementation of evidence-based intervention to treat and prevent HIV have risen top field's scientific priorities. Despite availability highly efficacious treatment prevention interventions, impact has fallen short targets because these interventions are used with insufficient reach, consistency, sustainability equity in diverse real-world settings. At present, substantial excitement for science - defined as research methods strategies improve use focused on developing disseminating conduct rigorous research. Yet, impactful answers depend a sometimes less visible, but even more important, step: asking good questions implementation.In this commentary, we offer several considerations researchers formulating based distinctive features field. First, findings not only by other implementers, must incorporate range stakeholder community perspectives be most relevant. Second, settings contextually diverse, relevant position make sense within contexts (whether geographical, organizational sociological), rather than apart from them. Third, is complex dynamic; consequently, emerging standards describing their effects whenever possible. Finally, field continues evolve, so framing problems disciplinary lens will enable pose insightful questions.We now at juncture marked both rich persistent global pandemic. To achieve continued progress against epidemic, right might part answer itself.

Язык: Английский

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