Antimicrobial Agents and Chemotherapy, Год журнала: 2021, Номер 65(5)
Опубликована: Фев. 23, 2021
The ability of HIV to integrate into the host genome and establish latent reservoirs is main hurdle preventing an cure. LEDGINs are small-molecule integrase inhibitors that target binding pocket LEDGF/p75, a cellular cofactor substantially contributes integration site selection.
Язык: Английский
Annual Review of Virology, Год журнала: 2021, Номер 8(1), С. 491 - 514
Опубликована: Сен. 29, 2021
Combinatory antiretroviral therapy (cART) reduces human immunodeficiency virus type 1 (HIV-1) replication but is not curative because cART interruption almost invariably leads to a rapid rebound of viremia due the persistence stable HIV-1-infected cellular reservoirs. These reservoirs are mainly composed CD4+ T cells harboring replication-competent latent proviruses. A broadly explored approach reduce HIV-1 reservoir size, shock and kill strategy, consists reactivating gene expression from latently infected (the shock), followed by killing virus-producing kill). Based on improved understanding multiple molecular mechanisms controlling latency, distinct classes latency reversing agents (LRAs) have been studied for their efficiency reactivate viral in vitro ex vivo cell models. Here, we provide an up-to-date review these different mechanistic LRAs discuss optimizations strategy combining several simultaneously or sequentially.
Язык: Английский
Процитировано
100
Nature Communications, Год журнала: 2021, Номер 12(1)
Опубликована: Сен. 20, 2021
Abstract Human Immunodeficiency Virus (HIV-1) produces a persistent latent infection. Control of HIV-1 using combination antiretroviral therapy (cART) comes at the cost life-shortening side effects and development drug-resistant HIV-1. An ideal safer should be deliverable in vivo target stable epigenetic repression virus, inducing “block lock” virus expression. Towards this goal, we developed an promoter-targeting Zinc Finger Protein (ZFP-362) fused to active domains DNA methyltransferase 3 A induce long-term Cells were engineered produce exosomes packaged with RNAs encoding repressor protein. We find here that loaded anti-HIV-1 suppress expression suppression is mechanistically driven by methylation humanized NSG mouse models. The observations presented pave way for exosome-mediated systemic delivery platform therapeutic cargo epigenetically repress
Язык: Английский
Процитировано
67
Frontiers in Cellular and Infection Microbiology, Год журнала: 2022, Номер 12
Опубликована: Июль 28, 2022
The persistence of latent reservoir the human immunodeficiency virus (HIV) is currently major challenge in curing HIV infection. After infects body, unable to be recognized by body’s immune system. Currently, widely adopted antiretroviral therapy (ART) also unble eliminate it, thus hindering progress treatment. This review discusses existence vault for treatment, its formation and factors affecting formation, cell, tissue localization, methods detection removing reservoir, provide a comprehensive understanding vault, order assist future research play potential role achieving
Язык: Английский
Процитировано
61
AIDS Research and Therapy, Год журнала: 2022, Номер 19(1)
Опубликована: Дек. 1, 2022
Abstract The development of antiretroviral therapy (ART) has been effective in suppressing HIV replication. However, severe drug toxicities due to the and its failure targeting integrated proviral genome have led introduction a new paradigm gene-based therapies. With inhibition high precision, clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein-9 nuclease (Cas9) or CRISPR/Cas9 emerged as an editing tool last decade. Mediated by guide RNAs (gRNAs), Cas9 endonuclease acts like genetic scissors that can modify specific target sites. this concept, used HIV-1 both vitro well vivo studies including non-human primates. CRISPR also tested for latent modulating transcription with help specialized mutant. Overcoming limitations current therapy, potential become primary eradicating infection. In review, we summarize recent advancements genome, challenges future prospects.
Язык: Английский
Процитировано
45
Viruses, Год журнала: 2024, Номер 16(7), С. 1163 - 1163
Опубликована: Июль 19, 2024
The latent reservoir remains a major roadblock to curing human immunodeficiency virus (HIV) infection. Currently available antiretroviral therapy (ART) can suppress active HIV replication, reduce viral loads undetectable levels, and halt disease progression. However, drugs are unable target cells that latently infected with HIV, which seed rebound if ART is stopped. Consequently, focus of the field study develop safe effective methods eliminate it. Here, we provide an overview mechanisms governing establishment maintenance latency, key challenges posed by reservoirs, small animal models utilized contemporary cure approaches. We also discuss ongoing efforts apply these approaches in combination, goal achieving safe, effective, scalable for be extended tens millions people worldwide.
Язык: Английский
Процитировано
11
Vaccines, Год журнала: 2021, Номер 9(8), С. 867 - 867
Опубликована: Авг. 5, 2021
Advances in antiretroviral therapy have prolonged the life of people living with HIV and diminished level virus these individuals. Yet, quickly rebounds after disruption and/or cessation treatment due to significant cellular anatomical reservoirs for HIV, which underscores challenge cure strategies. The central nervous system (CNS), particular, is seeded within 1–2 weeks infection a reservoir HIV. In this review, we address paradigm CNS relevant cell types, including astrocytes microglia, that been shown harbor viral even treatment. focus on developmental aspects microglia lead their susceptibility infection, how propagates among cells. We also challenges measuring latent reservoir, advances detection assays, curative strategies evolved regard reservoir. Current still require optimization reduce or eliminate may contribute levels neuroinflammation cognitive decline. With mind, brain should remain prominent when assessing options overall burden clinic, especially context HIV-associated neurocognitive disorders (HAND).
Язык: Английский
Процитировано
46
Current Opinion in Virology, Год журнала: 2023, Номер 59, С. 101301 - 101301
Опубликована: Фев. 17, 2023
Despite decades of suppressive antiretroviral therapy, human immunodeficiency virus (HIV) reservoirs in infected individuals persist and fuel viral rebound once therapy is interrupted. The persistence the main obstacle to achieving HIV eradication or a long-term remission. last decade has seen profound change our understanding mechanisms behind persistence, which appears be much more complex than originally assumed. In addition transcriptionally silent proviruses stable latent reservoir that invisible immune system, increasingly recognized by resistance clearance, play surprisingly prominent role shaping reservoir. this review, we discuss some emerging insights into as well their implications for development strategies towards an cure.
Язык: Английский
Процитировано
21
Phytomedicine, Год журнала: 2023, Номер 116, С. 154855 - 154855
Опубликована: Май 3, 2023
Язык: Английский
Процитировано
18
International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(5), С. 2621 - 2621
Опубликована: Фев. 23, 2024
Combination antiretroviral therapy (cART) has significantly improved the prognosis of individuals living with human immunodeficiency virus (HIV). Acquired syndrome transformed from a fatal disease to treatable chronic infection. Currently, effective and safe anti-HIV drugs are available. Although cART can reduce viral production in body patient below detection limit, it cannot eliminate HIV provirus integrated into host cell genome; hence, will be produced again after discontinuation. Therefore, research cure (or remission) for been widely conducted. In this review, we focus on drug development targeting cells latently infected assess progress including our current studies, particularly terms “Shock Kill”, “Block Lock” strategies.
Язык: Английский
Процитировано
9
Viruses, Год журнала: 2024, Номер 16(4), С. 500 - 500
Опубликована: Март 25, 2024
Autophagy has emerged as an integral part of the antiviral innate immune defenses, targeting viruses or their components for lysosomal degradation. Thus, successful viruses, like pandemic human immunodeficiency virus 1 (HIV-1), evolved strategies to counteract even exploit autophagy efficient replication. Here, we provide overview intricate interplay between and HIV-1. We discuss impact on HIV-1 replication report in detail how manipulates infected cells beyond. also highlight tissue cell-type specifics In addition, weigh exogenous modulation a putative double-edged sword against potential implications future antiretroviral therapy curative approaches. Taken together, consider both proviral roles illustrate ambivalent role pathogenesis therapy.
Язык: Английский
Процитировано
7