Next-generation bNAbs for HIV-1 cure strategies DOI Creative Commons

Angela I. Schriek,

Yoann Aldon, Marit J. van Gils

et al.

Antiviral Research, Journal Year: 2023, Volume and Issue: 222, P. 105788 - 105788

Published: Dec. 28, 2023

Despite the ability to suppress viral replication using anti-retroviral therapy (ART), HIV-1 remains a global public health problem. Curative strategies for have target and eradicate latently infected cells across body, i.e. reservoir. Broadly neutralizing antibodies (bNAbs) targeting envelope glycoprotein (Env) capacity neutralize virions bind initiate elimination of these cells. To improve efficacy bNAbs in terms suppression reservoir eradication, next generation (Abs) are being developed that address current limitations Ab treatment efficacy; (1) low antigen density on (reactivated) cells, (2) high genetic diversity, (3) exhaustion immune (4) short half-life Abs. In this review we summarize discuss preclinical clinical studies which anti-HIV-1 Abs demonstrated potent control, describe development engineered could described above. Next with optimized effector function, avidity, cell recruitment activation potential contribute an cure or durable control.

Language: Английский

Prevention, treatment and cure of HIV infection DOI
Raphael J. Landovitz, Hyman Scott, Steven G. Deeks

et al.

Nature Reviews Microbiology, Journal Year: 2023, Volume and Issue: 21(10), P. 657 - 670

Published: June 21, 2023

Language: Английский

Citations

81
The latent reservoir of inducible, infectious HIV-1 does not decrease despite decades of antiretroviral therapy DOI Creative Commons
Natalie F. McMyn, Joseph Varriale, Emily J. Fray

et al.

Journal of Clinical Investigation, Journal Year: 2023, Volume and Issue: 133(17)

Published: July 18, 2023

HIV-1 persists in a latent reservoir resting CD4+ T cells despite antiretroviral therapy (ART). The decays slowly over the first seven years of ART (t1/2 = 44 months). However, whether decay continues with long-term is unclear. Recent integration site studies indicate gradual selection against inducible, intact proviruses, raising speculation that decades might allow treatment interruption without viral rebound. Therefore, we measured 42 people on (mean 22 years) using quantitative outgrowth assay. After ART, there was no decrease frequency replication-competent proviruses but rather an increase estimated doubling time 23 years. Another assay, proviral DNA confirmed t1/2 months did not continue ART. lack reflected infected cell proliferation. Most (79.8%) viruses had env sequences identical to other isolates from same sample. Thus, although analysis indicates changes composition, proliferation counteracts decay, maintaining at roughly constant levels long term. These results reinforce need for lifelong

Language: Английский

Citations

60
Epigenetics-targeted drugs: current paradigms and future challenges DOI Creative Commons

Wanlin Dai,

Xinbo Qiao, Yuanyuan Fang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Nov. 26, 2024

Epigenetics governs a chromatin state regulatory system through five key mechanisms: DNA modification, histone RNA remodeling, and non-coding regulation. These mechanisms their associated enzymes convey genetic information independently of base sequences, playing essential roles in organismal development homeostasis. Conversely, disruptions epigenetic landscapes critically influence the pathogenesis various human diseases. This understanding has laid robust theoretical groundwork for developing drugs that target epigenetics-modifying pathological conditions. Over past two decades, growing array small molecule targeting such as methyltransferase, deacetylase, isocitrate dehydrogenase, enhancer zeste homolog 2, have been thoroughly investigated implemented therapeutic options, particularly oncology. Additionally, numerous epigenetics-targeted are undergoing clinical trials, offering promising prospects benefits. review delineates epigenetics physiological contexts underscores pioneering studies on discovery implementation drugs. include inhibitors, agonists, degraders, multitarget agents, aiming to identify practical challenges avenues future research. Ultimately, this aims deepen epigenetics-oriented strategies further application settings.

Language: Английский

Citations

30
Immune targeting of HIV-1 reservoir cells: a path to elimination strategies and cure DOI
Marie Armani-Tourret, Benjamin Bone, Toong Seng Tan

et al.

Nature Reviews Microbiology, Journal Year: 2024, Volume and Issue: 22(6), P. 328 - 344

Published: Feb. 9, 2024

Language: Английский

Citations

25
Time to HIV viral rebound and frequency of post-treatment control after analytical interruption of antiretroviral therapy: an individual data-based meta-analysis of 24 prospective studies DOI Creative Commons
Jesper Damsgaard Gunst, Jesal Gohil, Jonathan Z. Li

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 21, 2025

The only current strategy to test efficacy of novel interventions for sustained HIV control without antiretroviral therapy (ART) among people with (PWH) is through an analytical treatment interruption (ATI). Inclusion 'placebo' controls in ATIs poses ethical, logistical, and economic challenges. To understand viral dynamics rates post-treatment (PTC) after ATI PWH receiving either placebo or no intervention, we undertook individual-participant data meta-analysis. In total, 24 eligible prospective studies 382 individuals ≥5 plasma RNA loads (pVLs) within the first 84 days post-ATI were included. Early-ART was defined as ART initiation 6 months acquisition; others classified late-ART unknown. Median age 42 years, 91% male, 75% white, 45% received early-ART. time pVL >50, >400, >10,000 copies/mL 16 (interquartile range [IQR]:13–25), 21 (IQR:15–28), 32 (IQR:20–35), respectively. PTC <50 at day occurred 4% (n = 14) participants (6% early-ART 1% late-ART). Sustained copies/ml rare PWH, especially those starting late. Our findings inform future interventional cure/remission trials on study size design. Clinical testing treatments rely Using from studies, authors here show that virus becomes detectable around have HIV, providing information clinical trial

Language: Английский

Citations

2
Administration of broadly neutralizing anti-HIV-1 antibodies at ART initiation maintains long-term CD8+ T cell immunity DOI Creative Commons
Míriam Rosás-Umbert, Jesper Damsgaard Gunst, Marie H. Pahus

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Oct. 29, 2022

Abstract In simian-human immunodeficiency virus (SHIV)-infected non-human primates, broadly neutralizing antibodies (bNAbs) against the appear to stimulate T cell immunity. To determine whether this phenomenon also occurs in humans we measured HIV-1-specific cellular immunity longitudinally individuals with HIV-1 starting antiviral therapy (ART) or without adjunctive bNAb 3BNC117 treatment. Using activation-induced marker (AIM) assay and interferon-γ release, observe that frequencies of Pol- Gag-specific CD8 + cells, as well Gag-induced responses, are significantly higher among received compared ART-alone at 3 12 months after ART. The observed changes were directly correlated pre-treatment 3BNC117-sensitivity. Notably, increased is associated partial complete ART-free virologic control during treatment interruption for up 4 years. Our findings suggest time ART initiation maintains responses control.

Language: Английский

Citations

45
Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence: the randomized phase 2a TITAN trial DOI Creative Commons
Jesper Damsgaard Gunst, Jesper Falkesgaard Højen, Marie H. Pahus

et al.

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(10), P. 2547 - 2558

Published: Sept. 11, 2023

Abstract Inducing antiretroviral therapy (ART)-free virological control is a critical step toward human immunodeficiency virus type 1 (HIV-1) cure. In this phase 2a, placebo-controlled, double-blinded trial, 43 people (85% males) with HIV-1 on ART were randomized to (1) placebo/placebo, (2) lefitolimod (TLR9 agonist)/placebo, (3) placebo/broadly neutralizing anti-HIV-1 antibodies (bNAbs) or (4) lefitolimod/bNAb. interruption (ATI) started at week 3. Lefitolimod was administered once weekly for the first 8 weeks, and bNAbs twice, d before 3 weeks after ATI. The primary endpoint time loss of virologic median delay in compared placebo/placebo group 0.5 ( P = 0.49), 12.5 0.003) 9.5 0.004) lefitolimod/placebo, placebo/bNAb lefitolimod/bNAb groups, respectively. Among secondary endpoints, viral doubling slower bNAb groups non-bNAb interventions overall safe. We observed no added benefit lefitolimod. Despite subtherapeutic plasma levels, 36% (4/11) 0% (0/10) maintained 25-week Although immunotherapy did not lead ART-free control, may be important components future curative strategies. ClinicalTrials.gov identifier: NCT03837756 .

Language: Английский

Citations

33
Broadly neutralizing antibodies for HIV treatment and cure approaches DOI
Giacomo Schmidt Frattari, Marina Caskey, Ole S. Søgaard

et al.

Current Opinion in HIV and AIDS, Journal Year: 2023, Volume and Issue: 18(4), P. 157 - 163

Published: May 4, 2023

In recent years, clinical trials have explored broadly neutralizing antibodies (bNAbs) as treatment and cure of HIV. Here, we summarize the current knowledge, review latest studies, reflect on potential role bNAbs in future applications HIV strategies.In most individuals who switch from standard antiretroviral therapy to bNAb treatment, combinations at least two effectively suppress viremia. However, sensitivity archived proviruses neutralization maintaining adequate plasma levels are key determinants therapeutic effect. Combinations with injectable small-molecule antiretrovirals being developed long-acting regimens that may require little annual administrations maintain virological suppression. Further, interventions combine immune modulators or vaccines under investigation curative strategies. Interestingly, administration during early viremic stage infection appears enhance host responses against HIV.While accurately predicting resistant mutations has been a significant challenge for bNAb-based treatments, potent nonoverlapping epitopes help overcome this issue. As result, multiple strategies involving now investigated.

Language: Английский

Citations

28
The efficacy and tolerability of latency-reversing agents in reactivating the HIV-1 reservoir in clinical studies: a systematic review DOI Creative Commons
Quinten Debrabander, Kathryn S. Hensley, Christina Psomas

et al.

Journal of Virus Eradication, Journal Year: 2023, Volume and Issue: 9(3), P. 100342 - 100342

Published: Aug. 19, 2023

Understanding the clinical potency of latency reversing agents (LRAs) on HIV-1 reservoir is useful to deploy future LRA strategies. This systematic review evaluated effects LRAs in human intervention studies. A literature search was performed using medical databases focusing studies with adults living receiving LRAs. Eligibility criteria required participants from prospective studies, a studied compound hypothesised as LRA, and reactivation or tolerability assessments. Relevant demographical data, capacity, size, adverse events were extracted. study quality assessment analysis bias by RoB-2 ROBINS-I tools. The primary endpoints after treatment quantified cell-associated unspliced RNA, defined events. Secondary outcomes size effect analytical interruption (ATI) duration. After excluding duplicates, 5182 publications screened. In total 45 fulfilled eligibility including 26 16 randomised trials. risk high. Chromatin modulators main investigated class 24 Participants mostly males (90.1%). Where reported, subtype B most frequently observed. Reactivation occurred 78% observed nearly all chromatin modulators. When measured, within h initiation. Combination strategies have been infrequently without synergistic reactivation. Adverse events, where low grade yet frequently. Seven had individuals who discontinued for related assessed DNA 80% small decrease three immune checkpoint inhibitors histone deacetylase romidepsin chidamide. No clear ATI duration provides summary used current trials whilst highlighting importance pharmacovigilance. Highly heterogeneous designs underrepresentation relevant patient groups are be considered when interpreting these results. did not lead cure significant reduction reservoir. Finding more effective well-designed needed define level reduce

Language: Английский

Citations

26
Histone deacetylases and their inhibitors in inflammatory diseases DOI Open Access

Sen-Yu Zhang,

Liying Zhang, Ri Wen

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 179, P. 117295 - 117295

Published: Aug. 14, 2024

Despite considerable research efforts, inflammatory diseases remain a heavy burden on human health, causing significant economic losses annually. Histone deacetylases (HDACs) play role in regulating inflammation (via histone and non-histone protein deacetylation) chromatin structure gene expression regulation. Herein, we present detailed description of the different HDACs their functions analyze diseases, including pro-inflammatory cytokine production reduction, immune cell function modulation, anti-inflammatory activity enhancement. Although HDAC inhibitors have shown broad disease treatment potentials, clinical applicability remains limited because non-specific effects, adverse drug resistance. With further insight, these are expected to become important tools for wide range diseases. This review aims explore mechanisms application prospects multiple

Language: Английский

Citations

14