Program in Molecular Medicine; Department of Biochemistry and Molecular Pharmacology
Immune System Diseases | Immunity | Immunology of Infectious Disease | Immunoprophylaxis and Therapy | Molecular Biology | Virology | Virus Diseases | Viruses
HIV-1-infected people who take drugs that suppress viremia to undetectable levels are protected from developing AIDS. Nonetheless, these individuals have chronic inflammation associated with heightened risk of cardiovascular pathology. HIV-1 establishes proviruses in long-lived CD4+ memory T cells, and perhaps other cell types, that preclude elimination of the virus even after years of continuous antiviral therapy. Though the majority of proviruses that persist during antiviral therapy are defective for production of infectious virions, many are expressed, raising the possibility that the HIV-1 provirus or its transcripts contribute to ongoing inflammation. Here we found that the HIV-1 provirus activated innate immune signaling in isolated dendritic cells, macrophages, and CD4+ T cells. Immune activation required transcription from the HIV-1 provirus and expression of CRM1-dependent, Rev-dependent, RRE-containing, unspliced HIV-1 RNA. If rev was provided in trans, all HIV-1 coding sequences were dispensable for activation except those cis-acting sequences required for replication or splicing. These results indicate that the complex, post-transcriptional regulation intrinsic to HIV-1 RNA is detected by the innate immune system as a danger signal, and that drugs which disrupt HIV-1 transcription or HIV-1 RNA metabolism would add qualitative benefit to current antiviral drug regimens.
RNA, HIV-1, interferon, cytokines, inflammation
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The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.
DOI of Published Version
bioRxiv 128447; doi: https://doi.org/10.1101/128447. Link to preprint on bioRxiv service
McCauley, Sean M.; Kim, Kyusik; Nowosielska, Anetta; Dauphin, Ann; Yurkovetskiy, Leonid; Diehl, William E.; and Luban, Jeremy, "Intron-containing RNA from the HIV-1 provirus activates type I interferon and inflammatory cytokines" (2018). Program in Molecular Medicine Publications and Presentations. 84.
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