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A tissue-intrinsic mechanism sensitizes HIV-1 particles for TLR-triggered innate immune responses

ABSTRACT: In vivo, HIV-1 replicates within tissues, yet the impact of three-dimensional (3D) environments on viral spread remains poorly understood. We previously showed that collagen-rich 3D extracellular matrix (ECM) imposes an Environmental Restriction to cell-free Virus Infectivity (ERVI). Here, we demonstrate that ERVI is mediated by adhesive ECM components assembled into tissue-like scaffolds. Transient interactions with collagen fibers rapidly diminish virion infectivity across diverse primary strains by impairing virus fusogenicity. Notably, collagen-experienced particles also induce a distinct antiviral transcriptional program and strong pro-inflammatory cytokine secretion in monocyte-derived macrophages. Mechanistically, collagen contact induces conformational changes in the viral glycoprotein Env, enhances its interaction with toll-like receptor 2 (TLR2), and promotes trafficking into TLR8-positive endosomes, thereby amplifying innate immune sensing. Thus, ERVI acts through a dual mechanism: reducing virion fusogenicity while increasing innate immune detection. These findings identify the biophysical properties of the ECM as a tissue-intrinsic arm of antiviral innate immunity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE307977 | GEO | 2026/03/31

REPOSITORIES: GEO

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Project description:Influenza A virus (IAV) infection is a global respiratory disease, which annually leads to 3-5 million cases of severe illness, resulting in 290,000-650,000 deaths. Additionally, during the past century, four global IAV pandemics have claimed millions of human lives. The epithelial lining of the trachea plays a vital role during IAV infection, both as point of viral entry and replication as well as in the antiviral immune response. Tracheal tissue is generally inaccessible from human patients, which makes animal models crucial for the study of the tracheal host immune response. In this study, pigs were inoculated with swine- or human-adapted H1N1 IAV to gain insight into how host adaptation of IAV shapes the innate immune response during infection. In-depth multi-omics analysis (global proteomics and RNA sequencing) of the host response in upper and lower tracheal tissue was conducted, and results were validated by microfluidic qPCR. Additionally, a subset of samples was selected for histopathological examination. A classical innate antiviral immune response was induced in both upper and lower trachea after infection with either swine- or human-adapted IAV with upregulation of genes and higher abundance of proteins associated with viral infection and recognition, accompanied by a significant induction of interferon stimulated genes with corresponding higher proteins concentrations. Infection with the swine-adapted virus induced a much stronger immune response compared to infection with a human-adapted IAV strain in the lower trachea, which could be a consequence of a higher viral load and a higher degree of inflammation. Central components of the JAK-STAT pathway, apoptosis, pyrimidine metabolism, and the cytoskeleton were significantly altered depending on infection with swine- or human-adapted virus and might be relevant mechanisms in relation to antiviral immunity against putative zoonotic IAV. Based on our findings, we hypothesize that during host adaptation, IAV evolve to modulate important host cell elements to favor viral infectivity and replication.

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A tissue-intrinsic mechanism sensitizes HIV-1 particles for TLR-triggered innate immune responses

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