Biology subjects

Le Bury, G.

Publications and source records attributed to Le Bury, G..

3 recordsLinked to original sources

bioRxiv2026

Screening of epigenetic modifiers identifies novel host-directed agents that suppress HIV-1 replication in primary human macrophages

Epigenetic modifications play a critical role in diverse biological processes, including HIV-1 replication in lymphoid and myeloid cells, particularly in the establishment and maintenance of latency. As such, epigenetic targets represent potential candidates for novel host directed therapy (HDT). In this study, we developed a novel in vitro screening platform using human primary macrophages, including both monocyte-derived macrophages and alveolar macrophages, infected with a replication-competent luminescent virus. In contrast to previous screens, this platform enables the identification of compounds and epigenetic targets that modulate viral replication during a spreading infection, capturing not only transcriptional regulation but other vulnerabilities across the complete HIV-1 life cycle. Our data reveal multiple novel compounds targeting distinct epigenetic regulators, effectively inhibiting viral replication at various stages in primary macrophages, which may serve as potential candidates/targets for HDT.

immunology↗

bioRxiv2026

The lysosomal glutamine transporter SLC38A7/SNAT7 modulates SAMHD1 antiviral activity and promotes HIV-1 production in human macrophages

HIV-1 (Human Immunodeficiency Virus type 1) infects macrophages, which resist to the cytopathic effects of the virus and are considered as viral reservoirs. However, the cellular factors involved in viral production by human macrophages have not been fully identified. In this study, we focused on the amino acid transporter SNAT7 (small neutral amino-acid transporter 7), member of the SLC38 solute carrier family, which is the main lysosomal transporter of glutamine from the lysosome to the cytoplasm. Its expression was increased by HIV-1 infection. We revealed that the absence of SNAT7 inhibited viral production not only at the level of protein synthesis, but also early at the level of reverse transcription, without affecting global RNA or protein synthesis in the cells. The reduction in HIV expression upon SNAT7 depletion correlated with a reduction in the levels of an inactive form of the SAMHD1 (SAM domain- and HD domain-containing protein) restriction factor and was rescued following SAMHD1 degradation. Lastly, supplementation of the extracellular medium with glutamine in the absence of SNAT7 partially restored viral production. Together, our data reveal that glutamine extracted from lysosomes is involved in the early stages of the HIV-1 cycle and that the SNAT7 glutamine transporter acts as a dependency factor for HIV-1 in human macrophages.

microbiology↗

bioRxiv2024

Accessing anti-HIV activity through the attenuation of USP18 activity: novel insights from molecular dynamic simulations, free-energy profiling, and multi-cellular inhibition assays

The feasibility of achieving anti-HIV activity from the attenuation of USP18 activity was explored for the first time. A cheminformatic survey demonstrated that the current known USP18 isopeptidase inhibitors are derivatives of a bis-aryl pyranone scaffold that possesses undesirable toxicity profiles. Molecular modelling approaches applied to these active bis-aryl pyranones isolated the likely mechanism that perturbs the isopeptidase activity of USP18. Molecular dynamic simulations and free-energy profiling showed that induced-fit effects on the catalytic triad and the IBB-1 domain residues of USP18 drive a reversible non-competitive isopeptidase inhibition mechanism. Proof-of-concept multi-cellular HIV inhibition assays demonstrate the utility of achieving anti-HIV-1 activity from attenuating the activity of USP18 using small molecules. This study motivates for the pursuit of scaffolds that target the allosteric site of USP18, fine-tuning the IFN response as a strategy to enhance the natural control mechanisms that lead to an antiviral state potentially curing viral infection.

immunology↗