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

HIV cure: The daunting scale of the problem DOI Open Access
Janet D. Siliciano, Robert F. Siliciano

Science, Journal Year: 2024, Volume and Issue: 383(6684), P. 703 - 705

Published: Feb. 15, 2024

Cure strategies are confounded by basic reservoir biology.

Language: Английский

Citations

12
Selection of epigenetically privileged HIV-1 proviruses during treatment with panobinostat and interferon-α2a DOI Creative Commons
Marie Armani-Tourret, Ce Gao, Ciputra Adijaya Hartana

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(5), P. 1238 - 1254.e14

Published: Feb. 1, 2024

CD4+ T cells with latent HIV-1 infection persist despite treatment antiretroviral agents and represent the main barrier to a cure of infection. Pharmacological disruption viral latency may expose HIV-1-infected host immune activity, but clinical efficacy latency-reversing for reducing persistence remains be proven. Here, we show in randomized-controlled human trial that histone deacetylase inhibitor panobinostat, when administered combination pegylated interferon-α2a, induces structural transformation reservoir cell pool, characterized by disproportionate overrepresentation proviruses integrated ZNF genes chromatin regions reduced H3K27ac marks, molecular target sites panobinostat. By contrast, near marks were actively selected against, likely due increased susceptibility These data suggest can increase immunological vulnerability accelerate selection epigenetically privileged proviruses.

Language: Английский

Citations

11
Induction of durable remission by dual immunotherapy in SHIV-infected ART-suppressed macaques DOI
So‐Yon Lim, Jina Lee, Christa E. Osuna

et al.

Science, Journal Year: 2024, Volume and Issue: 383(6687), P. 1104 - 1111

Published: Feb. 29, 2024

The eradication of the viral reservoir represents major obstacle to development a clinical cure for established HIV-1 infection. Here, we demonstrate that administration N-803 (brand name Anktiva) and broadly neutralizing antibodies (bNAbs) results in sustained control after discontinuation antiretroviral therapy (ART) simian-human AD8 (SHIV-AD8)-infected, ART-suppressed rhesus macaques. N-803+bNAbs treatment induced immune activation transient viremia but only limited reductions SHIV reservoir. Upon ART discontinuation, rebound occurred all animals, which was followed by durable approximately 70% N-803+bNAb-treated Viral correlated with reprogramming CD8

Language: Английский

Citations

11
The Use of Broadly Neutralizing Antibodies (bNAbs) in HIV-1 Treatment and Prevention DOI Creative Commons

Jannifer Jasmin Thavarajah,

Bo Langhoff Hønge, Christian Wejse

et al.

Viruses, Journal Year: 2024, Volume and Issue: 16(6), P. 911 - 911

Published: June 4, 2024

Background: Although antiretroviral therapy (ART) effectively halts disease progression in HIV infection, the complete eradication of virus remains elusive. Additionally, challenges such as long-term ART toxicity, drug resistance, and demanding regimen daily lifelong adherence required by highlight imperative need for alternative therapeutic preventative approaches. In recent years, broadly neutralizing antibodies (bNAbs) have emerged promising candidates, offering potential therapeutic, preventative, possibly curative interventions against infection. Objective: This review aims to provide a comprehensive overview current state knowledge regarding passive immunization bNAbs HIV-1-infected individuals. Main findings: Recent findings from clinical trials highlighted treatment, prevention, quest an HIV-1 cure. While monotherapy with single bNAb is insufficient maintaining viral suppression preventing escape, ultimately leading rebound, combination potent, non-overlapping epitope-targeting demonstrated prolonged delayed time rebound restricting emergence escape mutations, albeit largely individuals bNAb-sensitive strains. has provided “proof concept” antibody-mediated prevention acquisition, although not been obtained. Therefore, further research on use treatment imperative.

Language: Английский

Citations

10
Integrative Assessment of Total and Intact HIV-1 Reservoir by a 5-Region Multiplexed Rainbow DNA Digital PCR Assay DOI Creative Commons
Mareva Delporte, Laurens Lambrechts, Evy Blomme

et al.

Clinical Chemistry, Journal Year: 2025, Volume and Issue: 71(1), P. 203 - 214

Published: Jan. 1, 2025

Persistent latent reservoirs of intact HIV-1 proviruses, capable rebounding despite suppressive antiretroviral therapy (ART), hinder efforts towards an cure. Hence, assays specifically quantifying proviruses are crucial to assess the impact curative interventions. Two recent have been utilized in clinical trials: proviral DNA assay (IPDA) and quadruplex quantitative PCR (Q4PCR). While IPDA is more sensitive due amplifying short fragments, it may overestimate fractions by relying only on quantification 2 regions. Q4PCR samples 4 regions, yet sequencing-based, favoring amplification shorter, hence non-intact, sequences.

Language: Английский

Citations

1
Autovaccination revisited: potential to boost antiviral immunity and facilitate HIV-1 cure/remission in children DOI
Helen Parker,

Julia E. Edgar,

Philip Goulder

et al.

Current Opinion in HIV and AIDS, Journal Year: 2025, Volume and Issue: unknown

Published: March 4, 2025

Purpose of review To the concept autovaccination as a strategy to boost anti-HIV-1 immunity and improve immune control, especially means facilitate cure/remission in paediatric HIV-1 infection, where effective interventions clinical testing remain limited compared adults. Recent findings Early studies, conducted 15–25 years ago, suggested potential immunological benefits from exposure autologous virus both children adults, specifically when antiretroviral therapy (ART) was initiated during acute infection. More recent work nonhuman primates (NHPs) has shown that early ART initiation can significantly reduce viral setpoint following treatment interruption, primarily through CD8 + T-cell responses, prevent escape - phenomenon commonly observed ART-naive infections. Additionally, NHP studies indicate multiple, short analytical interruptions (ATIs) delay rebound further lower via enhanced responses. Summary support for ATIs enhance antiviral control HIV-1. With well tolerated, monitored ATI protocols, could be valuable approach facilitating living with HIV (LWH), whom very early-ART early-life are associated low reservoirs high potential.

Language: Английский

Citations

1
Venetoclax, alone and in combination with the BH3 mimetic S63845, depletes HIV-1 latently infected cells and delays rebound in humanized mice DOI Creative Commons
Philip Arandjelovic, Youry Kim, James P. Cooney

et al.

Cell Reports Medicine, Journal Year: 2023, Volume and Issue: 4(9), P. 101178 - 101178

Published: Aug. 30, 2023

HIV-1 persists indefinitely in people living with HIV (PLWH) on antiretroviral therapy (ART). If ART is stopped, the virus rapidly rebounds from long-lived latently infected cells. Using a humanized mouse model of infection and CD4

Language: Английский

Citations

22
A histone deacetylase network regulates epigenetic reprogramming and viral silencing in HIV-infected cells DOI Creative Commons
Jackson J. Peterson, Catherine A. Lewis, Samuel D. Burgos

et al.

Cell chemical biology, Journal Year: 2023, Volume and Issue: 30(12), P. 1617 - 1633.e9

Published: Dec. 1, 2023

Language: Английский

Citations

18
The Effects of Human Immunodeficiency Virus Type 1 (HIV-1) Antigen-Expanded Specific T-Cell Therapy and Vorinostat on Persistent HIV-1 Infection in People With HIV on Antiretroviral Therapy DOI
Cynthia L. Gay, Patrick J. Hanley, Shane D. Falcinelli

et al.

The Journal of Infectious Diseases, Journal Year: 2024, Volume and Issue: 229(3), P. 743 - 752

Published: Feb. 13, 2024

Abstract Background The histone deacetylase inhibitor vorinostat (VOR) can reverse human immunodeficiency virus type 1 (HIV-1) latency in vivo and allow T cells to clear infected vitro. HIV-specific (HXTCs) be expanded ex have been safely administered people with HIV (PWH) on antiretroviral therapy. Methods Six PWH received infusions of 2 × 107 HXTCs/m² VOR 400 mg, 3 10 VOR. frequency persistent by multiple assays including quantitative viral outgrowth assay (QVOA) resting CD4+ was measured before after study Results HXTCs were safe, biomarkers serial effect detected, but enhanced antiviral activity circulating not evident. After VOR, 6 exhibited a decrease QVOA, all such declines However, most did exceed the 6-fold threshold needed definitively attribute decline intervention. Conclusions These modest effects provide support for strategy reversal reservoir clearance, more effective interventions are yield profound depletion likely clinical benefit. Clinical Trials Registration. NCT03212989.

Language: Английский

Citations

7
Utilizing immunotherapy towards achieving a functional cure for HIV-1 DOI

Fabrícia Heloisa Cavicchioli Sugiyama,

Lisa Loksø Dietz, Ole S. Søgaard

et al.

Current Opinion in HIV and AIDS, Journal Year: 2024, Volume and Issue: 19(4), P. 187 - 193

Published: April 11, 2024

Purpose of review Advancements in antiretroviral therapy (ART) have positively impacted the life expectancy and possibility living a normal for people with HIV-1. However, lifelong daily medication is necessary to prevent disease progression. To this end, immunotherapeutic strategies are being tested aim developing functional cure which immune system effectively controls HIV-1 absence ART. Recent findings The most promising advances achieving sustained remission or include broadly neutralizing antibodies (bNAbs) that administered alone combination other agents. Newer more innovative approaches redirecting T cells natural killer kill infected also shown results. Finally, multiple ongoing trials focus on combining bNAbs immune-directed therapies enhance both innate adaptive immunity. Summary While immunotherapies as an alternative conventional ART generally proven be well tolerated, these therapeutic largely been unsuccessful inducing ART-free control results from recent involving reported durable among subset participants, provide reason cautious optimism we further optimization treatment may able achieve

Language: Английский

Citations

5