Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence: the randomized phase 2a TITAN trial

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

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Immunoinformatic Identification of Multiple Epitopes of gp120 Protein of HIV-1 to Enhance the Immune Response against HIV-1 Infection

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(4), P. 2432 - 2432

Published: Feb. 19, 2024

Acquired Immunodeficiency Syndrome is caused by the Human Virus (HIV), and a significant number of fatalities occur annually. There dire need to develop an effective vaccine against HIV-1. Understanding structural proteins viruses helps in designing based on immunogenic peptides. In current experiment, we identified gp120 epitopes using bioinformatic epitope prediction tools, molecular docking, MD simulations. The Gb-1 peptide was considered adjuvant. Consecutive sequences GTG, GSG, GGTGG, GGGGS linkers were used bind B cell, Cytotoxic T Lymphocytes (CTL), Helper (HTL) epitopes. final construct consisted 315 amino acids expected be recombinant protein approximately 35.49 kDa. Based docking experiments, dynamics simulations, tertiary structure validation, analysis modeled indicates that it possesses stable can interact with Toll-like receptors. demonstrates proposed provoke immunological response activating cells, as well stimulating release IgA IgG antibodies. This shows potential for HIV-1 prophylaxis. in-silico design suggests multiple-epitope constructs potentially immunogens development.

Language: Английский

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Editorial: The global phenotypic diversity of HIV-1: implications for pathogenesis, vaccine, and cure

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 28, 2025

Despite the clinical success of antiretroviral therapy, there is no cure for HIV infection, yet. As reported, vaccines in development are early-stage trials (Haynes et al., 2023).Indeed, global and regional genetic diversity HIV-1 (i.e., its high mutation recombination rates) a main challenge vaccine development. Thus, investigating distribution subtypes/ clades different regions essential.To date, several immunotherapy approaches were considered to activate immune system (e.g., CD8 + T cells NK cells) eradicate latently HIV-infected elimination reservoir) including: a) reactivation using epigenetic modulators (Spivak Planelles, 2016;Kien Jonathan, 2024) or immunostimulators toll-like receptor (TLR) agonists) (Martinsen 2020;Rozman 2023); b) combination potent latency reversal agent Romidepsin) with an modulator therapeutic vaccine) (Mothe 2020 andRosas-Umbert 2020); c) use chimeric antigen receptors (CARs) directly killing (Hajduczki 2020;Zhou 2023). it critical determine which have important effect cells.At present, some studies aim develop preventive also overcome drug resistance as infection. Current management infection include prevention/ reversion viral latency, modulation responses, novel vaccines, improvement drugs patients (Deeks 2021;Maciel 2024).To address these areas management, this research topic/ special issue focused on: Altogether, complexity establishes increasing challenges preventive, functional towards goal end pandemic.We hope that four published scientific articles could provide new outlooks on studying AIDS from perspectives including testing before ART, longitudinal trajectory analysis multiple indicators, newer ART regimens early initiation PHIV, importance combined molecular surveillance epidemiology.The author declare was conducted absence any commercial financial relationships be construed potential conflict interest.

Language: Английский

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Immunological approaches to HIV cure

Seminars in Immunology, Journal Year: 2020, Volume and Issue: 51, P. 101412 - 101412

Published: Sept. 24, 2020

Combination antiretroviral therapy (ART) to treat human immunodeficiency virus (HIV) infection has proven remarkably successful – for those who can access and afford it yet HIV persists indefinitely in a reservoir of cells, despite effective ART host antiviral immune responses. An cure is therefore the next aspirational goal challenge, though approaches differ their objectives with 'functional cures' aiming durable viral control absence ART, 'sterilizing more difficult realize objective complete eradication. Mechanisms persistence, including latency, anatomical sequestration, suboptimal functioning, replenishment, target cell-intrinsic resistance, and, potentially, cell distraction effectors, likely need be overcome order achieve cure. A small fraction people living (PLWH) naturally via immune-mediated mechanisms, however, providing both sound rationale optimism that an immunological approach possible. Herein we review up date knowledge emerging evidence on: mechanisms contributing as well potential strategies these barriers; promising elimination reservoir-harboring harnessing adaptive responses engineered therapies, enhancers functions complementary innate functioning; combination are most succeed. Ultimately, must safe, effective, durable, eventually, scalable widely acceptable available.

Language: Английский

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The Role of Toll-Like Receptors in Retroviral Infection

Microorganisms, Journal Year: 2020, Volume and Issue: 8(11), P. 1787 - 1787

Published: Nov. 14, 2020

Toll-like receptors (TLRs) are key pathogen sensing that respond to diverse microbial ligands, and trigger both innate adaptive immune responses infection. Since their discovery, a growing body of evidence has pointed an important role for TLRs in retroviral infection pathogenesis. These data suggest multiple contribute the anti-retroviral response, TLR engagement by retroviruses can have complex divergent outcomes Despite this progress, numerous questions remain about In review, I summarize existing TLR-retrovirus interactions functional roles these play immunity pathogenesis, with particular focus on human immunodeficiency virus (HIV).

Language: Английский

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HBV/HIV Coinfection: Impact on the Development and Clinical Treatment of Liver Diseases

Frontiers in Medicine, Journal Year: 2021, Volume and Issue: 8

Published: Oct. 4, 2021

Hepatitis B virus (HBV) infection is a common contributor to chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Approximately 10% of people with human immunodeficiency (HIV) also have HBV co-infection, owing shared transmission routes. HIV/HBV coinfection accelerates the progression end-stage disease, or carcinoma compared mono-infection. HBV/HIV alters natural history hepatitis renders antiviral treatment more complex. In this report, we conducted critical review on epidemiology, history, pathogenesis diseases related coinfection. We summarized novel therapeutic options for these coinfected patients.

Language: Английский

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TLR agonists as vaccine adjuvants in the prevention of viral infections: an overview

Frontiers in Microbiology, Journal Year: 2023, Volume and Issue: 14

Published: Dec. 21, 2023

Tol-like receptor (TLR) agonists, as potent adjuvants, have gained attention in vaccine research for their ability to enhance immune responses. This study focuses on application improving efficacy against key viral infections, including hepatitis B virus (HBV), C (HCV), human immunodeficiency (HIV), SARS-CoV-2, influenza virus, and flaviviruses, West Nile dengue chikungunya virus. Vaccines are crucial preventing microbial viruses, adjuvants play a vital role modulating However, there still many diseases which effective vaccines lacking or limited response, posing significant threats health. The use of TLR agonists formulations holds promise effectiveness. By tailoring specific pathogens, such HBV, HCV, HIV, flavivirus, protective immunity chronic emerging infectious disease can be elicited.

Language: Английский

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Reverse vaccinology approaches to design a potent multiepitope vaccine against the HIV whole genome: immunoinformatic, bioinformatics, and molecular dynamics approaches

BMC Infectious Diseases, Journal Year: 2024, Volume and Issue: 24(1)

Published: Aug. 28, 2024

Substantial advances have been made in the development of promising HIV vaccines to eliminate HIV-1 infection. For first time, one hundred most submitted subtypes and CRFs were retrieved from LANL database, consensus sequences eleven proteins obtained design for human mouse hosts. By using various servers filters, highly qualified B-cell epitopes, as well HTL CD8 + epitopes that common between alleles also located conserved domains proteins, considered vaccine constructs. With 90% coverage worldwide, model covers a diverse allelic population, making it widely available. Codon optimization silico cloning prokaryotic eukaryotic vectors guarantee high expression models E. coli Molecular dynamics confirmed stable interaction constructs with TLR3, TLR4, TLR9, leading substantial immunogenic response designed vaccine. Vaccine effectively target humoral cellular immune systems humans mice; however, experimental validation is needed confirm these findings silico.

Language: Английский

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Combined noncanonical NF-κB agonism and targeted BET bromodomain inhibition reverse HIV latency ex vivo

Journal of Clinical Investigation, Journal Year: 2022, Volume and Issue: 132(8)

Published: April 14, 2022

Latency reversal strategies for HIV cure using inhibitor of apoptosis protein (IAP) antagonists (IAPi) induce unprecedented levels latent reservoir expression without immunotoxicity during suppressive antiretroviral therapy (ART). However, full targeting the may require combinatorial approaches. A Jurkat latency model screen IAPi combination partners demonstrated synergistic with bromodomain (BD) and extraterminal domain inhibitors (BETi). Mechanistic investigations CRISPR-CAS9 single-cell RNA-Seq informed comprehensive ex vivo evaluations plus pan-BET, bD-selective BET, or selective BET isoform in CD4+ T cells from ART-suppressed donors. IAPi+BETi treatment resulted striking induction cell-associated gag RNA, but lesser fully elongated tat-rev RNA compared cell activation–positive controls. bulk cultures an ultrasensitive p24 assay, did not result enhanced viral outgrowth frequency a standard quantitative assay. This study defines transcriptional elongation splicing as important barriers to following reversal, delineates roles proteins their BDs latency, provides rationale exploration animal models latency.

Language: Английский

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Breaking the Silence: Regulation of HIV Transcription and Latency on the Road to a Cure

Viruses, Journal Year: 2023, Volume and Issue: 15(12), P. 2435 - 2435

Published: Dec. 15, 2023

Antiretroviral therapy (ART) has brought the HIV/AIDS epidemic under control, but a curative strategy for viral eradication is still needed. The cessation of ART results in rapid rebound from latently infected CD4+ T cells, showing that control replication alone does not fully restore immune function, nor it eradicate reservoirs. With better understanding factors and mechanisms promote latency, current approaches are primarily focused on permanent silencing cells ("block lock") or reactivating HIV-1 gene expression combination with restoration strategies to eliminate HIV host ("shock kill"). In this review, we provide summary current, most promising cure strategies, including an analysis both latency-promoting agents (LPA) latency-reversing (LRA) have shown promise vitro, ex vivo, human clinical trials reduce reservoir.

Language: Английский

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