Work

The Impact of Defective HIV Proviruses on Innate Immune-Driven Inflammation 9022

Year: 2025

Type: article

Abstract: Description The persistent HIV reservoir includes a subset of cells harboring transcriptionally repressed latent HIV that contributes to rebound upon antiretroviral treatment (ART) interruption. Examination of proviral sequences shows the reservoir consists mostly of defective viral genomes with various mutations which would prevent production of HIV virions. People with HIV (PWH), even with suppression of viremia, demonstrate comorbidities of the central nervous system, heart, gut, and general aging-associated inflammation. These comorbidities are hypothesized to be driven by general inflammation and persistent circulation of pro-inflammatory cytokines. It is unclear if the latent HIV reservoir drives this inflammation. We previously demonstrated that transcription initiates from a promoter-like element located within HIV envelope gene. To investigate the impact of these transcripts, we employed CRISPR-cas9 to engineer cells harboring HIV genomes with a non-functional 5’ Long Terminal Repeat (LTR), which acts as the enhancer and promoter for HIV proviral transcription. We observe a correlation between the levels of these internally driven transcripts with production of pro-inflammatory cytokines in vitro using macrophage-like cells (THP1), monocyte-derived-macrophages, and mononuclear cells obtained from PWH on ART. Knocking out MAVS abrogated this effect. We propose that defective HIV proviruses actively contribute to chronic inflammation in PWH via a MAVS-dependent pathway. Funding Sources Supported by: NIH grant R01 AI187175; NIH grant R01 AI138960; NIH grant R01 DA055488; CFAR P30AI042853 Topic Categories Viral Immunology (VIR)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkaf283.2486