An Environmental Restriction impairs HIV-1 virion fusion and triggers innate immune recognition

In vivo, HIV-1 replicates within 3D tissues, yet the impact of tissue-like environments on viral spread is largely unknown. Our previous research identified that synthetic 3D environments impose an Environmental Restriction to cell-free Virus Infectivity (ERVI) that diminishes HIV-1 particle infectivity. Here, mechanistic studies reveal that ERVI is implemented within minutes, saturable and induced by different adhesive tissue-like 3D matrices. ERVI reduces infectivity across a wide range of primary HIV-1 strains and virions bearing distinct viral glycoproteins but does not damage virion morphology or affect their binding to target cells. Rather, ERVI impairs virion fusion with target cells and infectivity enhancing peptide nanofibrils can restore efficient infection. In addition, ERVI sensitizes HIV-1 particles for recognition by monocyte-derived macrophages via toll-like receptors 4 and 8, triggering pronounced pro-inflammatory cytokine secretion. These results suggest that ERVI represents a broadly acting, tissue-intrinsic barrier to virus spread that reduces the fusogenicity of cell-free virions and sensitizes them for innate immune recognition.