Innate Immune Sensing of HIV Defective Provirus Transcripts Contributes to Chronic Inflammation 2266501

Abstract

The persistent HIV reservoir includes latently infected cells, which upon antiretroviral treatment (ART) interruption, reactivate HIV-1 expression and fuel rebound of disease progression. People living with HIV, even on ART, experience chronic inflammation associated with accelerated aging and comorbidities of the central nervous system, gut, and heart. The persistent reservoir is mostly composed of defective proviral genomes, unable to produce infectious virus due to deleterious mutations. However, the contribution of these defective viruses to chronic disease has not been well characterized. We have demonstrated that an intragenic element in the Env region of the HIV genome drives transcription of non-canonical RNA in defective proviruses. We hypothesize that these transcripts from defective proviruses contribute to chronic inflammation. To model defective proviruses, we used CRISPR-Cas9 to engineer cells harboring HIV genomes with a nonfunctional 5’ LTR. We observed a correlation between levels of internally driven transcripts and in vitro pro-inflammatory cytokine production in Jurkats, macrophage-like ThP1 cells, and cells differentiated into macrophages. Additionally, we confirmed nuclear export of these transcripts and that shRNA-mediated MAVS knockdown in ThP1s decreases the inflammatory response. We propose a model that innate immune sensing of these transcripts activates a MAVS-dependent pathway to contribute to chronic inflammation and HIV-associated comorbidities. NIH RO1 AI187175, NIH RO1 AI138960, NIH RO1 DA055488, CFAR P30AI042853, Boston University Undergraduate Research Opportunities Program Faculty Matching Grant Viral Immunology (VIR)