5' cap sequestration is required for sensing of unspliced HIV-1 RNA by MDA5.

ABSTRACT: Heterogenous transcription start site (TSS) usage dictates the structure and function of unspliced HIV-1 RNAs (usRNA). We and others have previously reported that expression and Rev/CRM1-mediated nuclear export of HIV-1 usRNA in macrophages activates MDA5, MAVS, and innate immune signaling cascades. In this study, we reveal that MDA5 sensing of viral usRNA is strictly determined by TSS, 5' leader structure, and RNA function. We show that cap-sequestered HIV-1 usRNAs (^cap1G) destined for viral genome packaging are specifically targeted by MDA5, while translation-destined (^cap3G) usRNAs are remarkably immunologically silent. Using mutant viruses which express usRNA with altered 5' cap-exposed leader structure, or inclusion of a retroviral constitutive transport element

SUBMITTER: Hughes IK 

PROVIDER: S-EPMC12407712 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature