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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Breaking Barriers to an HIV-1 Cure: Innovations in Gene Editing, Immune Modulation, and Reservoir Eradication

Life, Journal Year: 2025, Volume and Issue: 15(2), P. 276 - 276

Published: Feb. 11, 2025

Recent advances in virology, particularly the study of HIV-1, have significantly progressed pursuit a definitive cure for disease. Emerging therapeutic strategies encompass innovative gene-editing technologies, immune-modulatory interventions, and next-generation antiretroviral agents. Efforts to eliminate or control viral reservoirs also gained momentum, with aim achieving durable remission without continuous requirement therapy. Despite these promising developments, critical challenges persist bridging gap between laboratory findings clinical implementation. This review provides comprehensive analysis recent breakthroughs, ongoing trials, barriers that must be addressed translate advancements into effective treatments, emphasizing multifaceted approaches being pursued achieve curative solution HIV-1 infection.

Language: Английский

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Harnessing immune cells to eliminate HIV reservoirs

Current Opinion in HIV and AIDS, Journal Year: 2024, Volume and Issue: 19(2), P. 62 - 68

Published: Jan. 2, 2024

Purpose of review Despite decades insights about how CD8 + T cells and natural killer (NK) contribute to control infection, additional hurdles (mutational escape from cellular immunity, sequence diversity, hard-to-access tissue reservoirs) will need be overcome develop a cure. In this review, we highlight recent findings novel mechanisms antiviral immunity discuss current strategies for therapeutic deisgn. Recent Of note are the apparent converging roles viral antigen-specific MHC-E-restricted NK cells, interleukin (IL)-15 biologics boost cytotoxicity, broadly neutralizing antibodies in their native form or as anitbody fragments neutralize virus engage respectively. Finally, renewed interest myeloid relevant reservoirs is an encouraging sign designing inclusive strategies. Summary Several studies have shown promise many preclinical models disease, including simian immunodeficiency (SIV)/SHIV infection nonhuman primates HIV humanized mice. However, each model comes with its own limitations may not fully predict human responses. We eagerly await results clinical trails assessing efficacy these achieve reductions reservoirs, delay rebound, ultimately elicit immune based without combination antiretroviral therapy (cART).

Language: Английский

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Post-Transcriptional HIV-1 Latency: A Promising Target for Therapy?

Viruses, Journal Year: 2024, Volume and Issue: 16(5), P. 666 - 666

Published: April 24, 2024

Human Immunodeficiency Virus type 1 (HIV-1) latency represents a significant hurdle in finding cure for HIV-1 infections, despite tireless research efforts. This challenge is partly attributed to the intricate nature of latency, wherein various host and viral factors participate multiple physiological processes. While substantial progress has been made discovering therapeutic targets transcription, post-transcriptional regulation infections have received less attention. However, cumulative evidence now suggests pivotal contribution both vitro models infected individuals. In this review, we explore recent insights on discuss potential its targets, illustrating some that restrict at level.

Language: Английский

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From natural defenders to therapeutic warriors: NK cells in HIV immunotherapy

Immunotherapy, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 13

Published: Feb. 5, 2025

Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells both play essential roles in controlling viral infections by eliminating virus-infected cells. Unlike CTLs, which require priming activation antigen-presenting cells, NK possess a remarkable capacity to mount rapid antiviral immune response immediately after infection. Additionally, they can bolster the adaptive system secreting cytokines directly interacting with other However, during chronic human immunodeficiency virus (HIV) infection, various including experience functional impairments. This has led exploration of cell-based immunotherapy as promising strategy reverse these dysfunctions contribute pursuit cure for HIV. Building on success cell therapies cancer treatment, approaches offer significant potential transforming HIV field. review provides comprehensive overview latest advances HIV, outlining progress made key challenges that must be overcome achieve people living

Language: Английский

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Activating PKC-ε induces HIV expression with improved tolerability

PLoS Pathogens, Journal Year: 2025, Volume and Issue: 21(2), P. e1012874 - e1012874

Published: Feb. 6, 2025

Despite suppressive antiretroviral therapy (ART), HIV-1 persists in latent reservoirs that seed new HIV infections if ART is interrupted, necessitating lifelong for people with HIV. Activation of during could improve recognition and elimination infected cells by the immune system. Protein kinase C (PKC) isozymes increase transcription hence are potential latency reversal agents. However, clinical utility PKCs this application limited due to toxicity, which poorly understood. Our studies showed PKC activation multiple classes agonists leads widespread platelet activation, consistent disseminated intravascular coagulation, at concentrations were similar those required T-cell activation. Differential expression analysis indicated PKC-ε PKC-η isoforms expressed high levels human CD4 + T but not platelets. Using structure-based drug design, we developed a novel agonist, C-233, increased selectivity PKC-ε. C-233 both supernatant RNA p24 ex vivo after treatment from ART-suppressed was 5-fold more potent relative support use design create selective safe improved tolerability.

Language: Английский

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Targeting Latent HIV Reservoirs: Effectiveness of Combination Therapy with HDAC and PARP Inhibitors

Viruses, Journal Year: 2025, Volume and Issue: 17(3), P. 400 - 400

Published: March 12, 2025

The “Kick and Kill” strategy, which aims to reactivate latent HIV reservoirs facilitate the clearance of reactivated HIV-infected cells, has yet achieve a functional cure due limited efficacy current latency reversal agents. This study evaluates combination histone deacetylase (HDAC) inhibitor with poly(ADP-ribose) polymerase (PARP) in immune-mediated clearance. Latently infected J-Lat cells dual-fluorescent primary CD4 T were treated HDAC (vorinostat) one four PARP inhibitors (olaparib, rucaparib, niraparib, or talazoparib). inhibitors, when administered alone, showed no activity. However, combined vorinostat, their increased threefold compared vorinostat alone. effect was mediated by inhibition tankyrase, superfamily member, modulates Hippo signaling pathway. In HIVGR670-infected reduced reservoir size 67%. addition, talazoparib alone significantly actively 50%. Talazoparib-treated peripheral blood mononuclear co-cultured K562 demonstrated enhanced NK-cell-mediated cytotoxicity, 10% reduction cell viability. These findings demonstrate that combining augments reduction. With both used this approved FDA for cancer treatment, therapy holds strong potential rapid clinical integration, contingent upon confirmation safety ongoing vivo studies.

Language: Английский

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

Published: March 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.

Language: Английский

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Integration of long-acting antiretroviral therapies and latency-reversing agents for reservoir reduction and viral suppression: a comprehensive review

InterConf, Journal Year: 2025, Volume and Issue: 53(232), P. 258 - 270

Published: Jan. 20, 2025

Despite significant advancements in antiretroviral therapy (ART), the persistent latent HIV reservoir remains a major barrier to achieving complete cure. Current ART regimens effectively suppress viral replication but necessitate lifelong adherence due their inability eradicate HIV. Long-acting therapies (LA-ARTs) have emerged as an innovation improve and reduce burden of daily dosing. Additionally, latency-reversing agents (LRAs) aim reactivate virus, making it susceptible immune clearance. The combination LA-ART LRAs offers promising therapeutic approach address both challenges eradication. Objective: This review explores potential synergy between LRAs, focusing on individual combined roles reducing reservoirs sustaining suppression. Methodology: A systematic search peer-reviewed articles clinical studies was conducted following SANRA guidelines. Inclusion criteria included involving PLWH, and/or evaluating outcomes such reduction Studies without applicability or reporting relevant were excluded. Discussion: enhances quality life by dosing frequency, while utilize “shock kill” strategy virus. potential, suboptimal LRA efficacy, clearance limitations, accessibility barriers persist. Combining these may create robust treatment framework, further research is needed optimize overcome implementation challenges. highlights need for collaborative efforts policy refine integrate therapies, moving closer functional cure

Language: Английский

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

eLife, Journal Year: 2025, Volume and Issue: 13

Published: April 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.

Language: Английский

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