Dataset Information

Novel TLR7/8 agonists promote activation of HIV-1 latent reservoirs and human T and NK cells.

ABSTRACT: Antiretroviral therapy can successfully suppress HIV-1 replication to undetectable levels but fails to eliminate latent and persistent HIV-1 reservoirs. Recent studies have focused on the immunomodulatory agents such as Toll-like receptor 7 and 8 (TLR7 and TLR8) capable of activating, thereby rendering the reservoir susceptible to antiretroviral inhibition and immune recognition and elimination. In this context, this study focused on generating a diverse repertoire of TLR7/8 agonists to identify more potent candidates for activating latent HIV-1 and immune cells' response. Through combinational strategies of computer-aided design and biological characterization, 159 pyrido [3,2-d] pyrimidine and pyridine-2-amine-based derivatives were synthesized. Of which, two TLR7/8 dual and one TLR8-specific agonists with exceptionally high potency in activating HIV-1 latent reservoirs in cell lines and PBMCs of patients with persistent and durable virologic controls were identified. Particularly, these agonists appeared to enhance NK and T cells activity, which were correlated with the degree of surface activation markers. The outcome of this study highlights the remarkable potential of TLR7/8 agonists in simultaneously activating HIV-1 from the latently infected cells and augmenting immune effector cells.

SUBMITTER: Li Y

PROVIDER: S-EPMC9911797 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Novel TLR7/8 agonists promote activation of HIV-1 latent reservoirs and human T and NK cells.

Li Yangyang Y Wang Zhisong Z Hou Ying Y Liu Xiaoyu X Hong Junxian J Shi Xuanling X Huang Xiaojie X Zhang Tong T Liao Xuebin X Zhang Linqi L

Frontiers in microbiology 20230127

Antiretroviral therapy can successfully suppress HIV-1 replication to undetectable levels but fails to eliminate latent and persistent HIV-1 reservoirs. Recent studies have focused on the immunomodulatory agents such as Toll-like receptor 7 and 8 (TLR7 and TLR8) capable of activating, thereby rendering the reservoir susceptible to antiretroviral inhibition and immune recognition and elimination. In this context, this study focused on generating a diverse repertoire of TLR7/8 agonists to identify ...[more]

PMID: 36778871

Similar Datasets

Project description:Immunostimulatory therapies based on pattern recognition receptors (PRRs) have emerged as an effective approach in the fight against cancer, with the ability to recruit tumor-specific lymphocytes in a low-immunogenicity tumor environment. The agonist cyclic dinucleotides (CDNs) of the stimulator of interferon gene (STING) are a group of very promising anticancer molecules that increase tumor immunogenicity by activating innate immunity. However, the tumor immune efficacy of CDNs is limited by several factors, including relatively narrow cytokine production, inefficient delivery to STING, and rapid clearance. In addition, a single adjuvant molecule is unable to elicit a broad cytokine response and thus cannot further amplify the anticancer effect. To address this problem, two or more agonist molecules are often used together to synergistically enhance immune efficacy. In this work, we found that a combination of the STING agonist CDGSF and the Toll-like receptor 7/8 (TLR7/8) agonist 522 produced a broader cytokine response. Subsequently, we developed multicomponent nanovaccines (MCNVs) consisting of a PC7A polymer as a nanocarrier encapsulating the antigen OVA and adjuvant molecules. These MCNVs activate bone marrow-derived dendritic cells (BMDCs) to produce multiple proinflammatory factors that promote antigen cross-presentation to stimulate specific antitumor T-cell responses. In in vivo experiments, we observed that MCNVs triggered a strong T-cell response in tumor-infiltrating lymphocytes, resulting in significant tumor regression and, notably, a 100% survival rate in mice through 25 days without other partnering therapies. These data suggest that our nanovaccines have great potential to advance cancer immunotherapy with increased durability and potency.Electronic supplementary materialSupplementary material (synthesis of CDGSF, 522, PC7A and OVA; preparation of MCNVs; representative gating strategies for flow cytometry) is available in the online version of this article at 10.1007/s12274-022-4282-x.

Dataset Information

Novel TLR7/8 agonists promote activation of HIV-1 latent reservoirs and human T and NK cells.

Publications

Novel TLR7/8 agonists promote activation of HIV-1 latent reservoirs and human T and NK cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets