HIV Persistence, Latency, and Cure Approaches: Where Are We Now?

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

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Integrator complex subunit 12 knockout overcomes a transcriptional block to HIV latency reversal

Опубликована: Март 26, 2025

The latent HIV reservoir is a major barrier to cure. Combining latency reversal agents (LRAs) with differing mechanisms of action such as AZD5582, non-canonical NF-kB activator, and I-BET151, bromodomain inhibitor appealing towards inducing HIV-1 reactivation. However, even this LRA combination needs improvement it inefficient at activating proviruses in cells from people living (PLWH). We performed CRISPR screen conjunction AZD5582 & I-BET151 identified member the Integrator complex target improve combination, specifically subunit 12 (INTS12). functions genome-wide attenuator transcription that acts on elongation through its RNA cleavage phosphatase modules. Knockout INTS12 improved reactivation transcriptional level more specific provirus than treatment alone. found present chromatin promoter therefore effect may be direct. Additionally, we observed RNAPII gene body only knockout indicating induces block viral Moreover, increased CD4 T virally suppressed PLWH ex vivo , detected supernatant all three tested upon suggesting prevents full-length production primary cells. Finally, generally limits efficacy variety LRAs different action.

Язык: Английский

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Integrator complex subunit 12 knockout overcomes a transcriptional block to HIV latency reversal

eLife, Год журнала: 2025, Номер 13

Опубликована: Апрель 10, 2025

The latent HIV reservoir is a major barrier to cure. Combining latency reversal agents (LRAs) with differing mechanisms of action such as AZD5582, non-canonical NF-kB activator, and I-BET151, bromodomain inhibitor appealing toward inducing HIV-1 reactivation. However, even this LRA combination needs improvement it inefficient at activating proviruses in cells people living (PLWH). We performed CRISPR screen conjunction AZD5582 & I-BET151 identified member the Integrator complex target improve combination, specifically subunit 12 (INTS12). functions genome-wide attenuator transcription that acts on elongation through its RNA cleavage phosphatase modules. Knockout INTS12 improved reactivation transcriptional level more specific provirus than treatment alone. found present chromatin promoter therefore effect may be direct. Additionally, we observed RNAPII gene body only knockout indicating induces block viral Moreover, increased CD4 T from virally suppressed PLWH ex vivo, detected supernatant all three tested upon knockout, suggesting prevents full-length production primary cells. Finally, generally limits efficacy variety LRAs different action.

Язык: Английский

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Epitranscriptomic m ⁶ A modifications during reactivation of HIV-1 latency in CD4 ⁺ T cells

mBio, Год журнала: 2024, Номер 15(11)

Опубликована: Окт. 7, 2024

ABSTRACT Despite effective antiretroviral therapy reducing HIV-1 viral loads to undetectable levels, the presence of latently infected CD4 + T cells poses a major barrier cure. N 6 -methyladenosine (m A) modification and cellular RNA has functional role in regulating infection. m A can affect its stability, translation, splicing suppresses type-I interferon induction macrophages. However, function latency reactivation remains unknown. We used Jurkat cell line-derived model (J-Lat cells) investigate changes levels response reversal. observed significant increase total upon latent J-Lat cells. This was transient returned steady-state despite continued high gene expression reactivated compared control Upregulation occurred without protein writers or erasers that add remove A, respectively. Knockdown significantly reduced reactivation. Treatment with an writer inhibitor along reduction Furthermore, using A-specific sequencing, we identified RNAs are differentially A-modified during validates these results established primary latency. These show importance IMPORTANCE is important for innate immune responses significance To address this question, study, models latency, sequencing at single-base resolution, assays. demonstrate reversal leads increased modification, correlates dependent on catalytic activity methyltransferase enzyme. also genes reactivation, as well sites within RNA. Our novel findings point toward

Язык: Английский

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Deep Thought on the HIV Cured Cases: Where Have We Been and What Lies Ahead?

Biomolecules, Год журнала: 2025, Номер 15(3), С. 378 - 378

Опубликована: Март 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.

Язык: Английский

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A targeted CRISPR screen identifies ETS1 as a regulator of HIV-1 latency

PLoS Pathogens, Год журнала: 2025, Номер 21(4), С. e1012467 - e1012467

Опубликована: Апрель 8, 2025

Human Immunodeficiency virus (HIV) infection is regulated by a wide array of host cell factors that combine to influence viral transcription and latency. To understand the complex relationship between HIV-1 latency, we performed lentiviral CRISPR screen targeted set genes whose expression or activity correlates with expression. We further investigated one identified - factor ETS1, found it required for maintenance latency in both latently infected lines primary CD4 T model. Interestingly, ETS1 played divergent roles actively cells, knockout leading reduced but increased indicating can play positive negative role CRISPR/Cas9 cells from ART-suppressed people (PWH) confirmed maintains transcriptional repression clinical reservoir. Transcriptomic profiling ETS1-depleted PWH pathways involved are controlled resting cells. In particular, observed long non-coding RNA MALAT1 has been previously as regulator Furthermore, impact depletion on was partially dependent MALAT1. Additionally, demonstrate resulted enhanced abundance activating modifications (H3K9Ac, H3K27Ac, H3K4me3) histones located at terminal repeat (LTR), regulates chromatin-targeting complexes LTR. Overall, these data an important impacts through repressing regulating modification proviral histones.

Язык: Английский

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Zoledronic acid: challenges and pitfalls amid rehabilitation in primary osteoporosis and beyond

Balneo and PRM Research Journal, Год журнала: 2024, Номер 15(Vol.15, no. 2), С. 704 - 704

Опубликована: Июнь 21, 2024

Zoledronate (or zoledronic acid) represents a standard (guideline-based) approach in the area of anti-resorptive medication (namely, an annual 15-minute perfusion 5 mg for os-teoporosis treatment), while same drug (with doses/regimes variations) is used other bone metabolic conditions such as Paget’s disease or skeleton metastasis originating from different cancers. The objective this narrative review was to highlight most recent published data with respect acid use part complex clinical management amid primary osteoporosis addition osteo-metabolic clin-ical entities. This research based on exploring PubMed database search words “zoledronic acid” and “primary osteoporosis”. We included highly relevant (from perspective), English-published, full-length articles that have been re-cently (between January 2023 March 2024). From 249 results, 31 met inclusion timeline criteria across 15-month analysis final results were provided 16 articles. Important insights concern not only administration, efficacy safety profile, but, also, extension daily indications diabetic disease, liver osteodystrophy, osteogen-esis imperfecta bone. Keywords: osteoporosis, rehabilitation, acid, DXA, hypercalcemia, bone, surgery, prosthesis, osteodystrophy

Язык: Английский

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Integrator complex subunit 12 knockout overcomes a transcriptional block to HIV latency reversal

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 31, 2024

The latent HIV reservoir is a major barrier to cure. Combining latency reversal agents (LRAs) with differing mechanisms of action such as AZD5582, non-canonical NF-kB activator, and I-BET151, bromodomain inhibitor appealing towards inducing HIV-1 reactivation. However, even this LRA combination needs improvement it inefficient at activating proviruses in cells from people living (PLWH). We performed CRISPR screen conjunction AZD5582 & I-BET151 identified member the Integrator complex target improve combination, specifically subunit 12 (INTS12). functions genome-wide attenuator transcription that acts on elongation through its RNA cleavage phosphatase modules. Knockout INTS12 improved reactivation transcriptional level more specific provirus than treatment alone. found present chromatin promoter therefore effect may be direct. Additionally, we observed RNAPII gene body only knockout indicating induces block viral Moreover, increased CD4 T virally suppressed PLWH ex vivo , detected supernatant all three tested upon suggesting prevents full-length production primary cells. Finally, generally limits efficacy variety LRAs different action.

Язык: Английский

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Integrator complex subunit 12 knockout overcomes a transcriptional block to HIV latency reversal

Опубликована: Ноя. 21, 2024

The latent HIV reservoir is a major barrier to cure. Combining latency reversal agents (LRAs) with differing mechanisms of action such as AZD5582, non-canonical NF-kB activator, and I-BET151, bromodomain inhibitor appealing towards inducing HIV-1 reactivation. However, even this LRA combination needs improvement it inefficient at activating proviruses in cells from people living (PLWH). We performed CRISPR screen conjunction AZD5582 & I-BET151 identified member the Integrator complex target improve combination, specifically subunit 12 (INTS12). functions genome-wide attenuator transcription that acts on elongation through its RNA cleavage phosphatase modules. Knockout INTS12 improved reactivation transcriptional level more specific provirus than treatment alone. found present chromatin promoter therefore effect may be direct. Additionally, we observed RNAPII gene body only knockout indicating induces block viral Moreover, increased CD4 T virally suppressed PLWH ex vivo . also detected supernatant all three tested upon suggesting prevents full-length production primary cells.

Язык: Английский

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Integrator complex subunit 12 knockout overcomes a transcriptional block to HIV latency reversal

Опубликована: Ноя. 21, 2024

The latent HIV reservoir is a major barrier to cure. Combining latency reversal agents (LRAs) with differing mechanisms of action such as AZD5582, non-canonical NF-kB activator, and I-BET151, bromodomain inhibitor appealing towards inducing HIV-1 reactivation. However, even this LRA combination needs improvement it inefficient at activating proviruses in cells from people living (PLWH). We performed CRISPR screen conjunction AZD5582 & I-BET151 identified member the Integrator complex target improve combination, specifically subunit 12 (INTS12). functions genome-wide attenuator transcription that acts on elongation through its RNA cleavage phosphatase modules. Knockout INTS12 improved reactivation transcriptional level more specific provirus than treatment alone. found present chromatin promoter therefore effect may be direct. Additionally, we observed RNAPII gene body only knockout indicating induces block viral Moreover, increased CD4 T virally suppressed PLWH ex vivo . also detected supernatant all three tested upon suggesting prevents full-length production primary cells.

Язык: Английский

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