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<p>In vivo, HIV-1 replicates within tissues, yet the impact of three-dimensional (3D) environments on viral spread remains unclear. Our laboratory 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 functions 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月9日

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  • Samy Sid Ahmed,
  • Liv Zimmermann,
  • Andrea Imle,
  • Katrin Wuebben,
  • Nadine Tibroni,
  • Lena Rauch-Wirth,
  • Jan Münch,
  • Petr Chlanda,
  • Frederik Graw,
  • Oliver T. Fackler

摘要

In vivo, HIV-1 replicates within tissues, yet the impact of three-dimensional (3D) environments on viral spread remains unclear. Our laboratory 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 functions 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.