Intron-containing RNA from the HIV-1 provirus activates type I interferon and inflammatory cytokines

Sean Matthew McCauley, Kyusik Kim, Anetta Nowosielska, Ann Dauphin, Leonid Yurkovetskiy, William Edward Diehl and Jeremy Luban ()
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Sean Matthew McCauley: University of Massachusetts Medical School
Kyusik Kim: University of Massachusetts Medical School
Anetta Nowosielska: University of Massachusetts Medical School
Ann Dauphin: University of Massachusetts Medical School
Leonid Yurkovetskiy: University of Massachusetts Medical School
William Edward Diehl: University of Massachusetts Medical School
Jeremy Luban: University of Massachusetts Medical School

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: Abstract HIV-1-infected people who take drugs that suppress viremia to undetectable levels are protected from developing AIDS. Nonetheless, 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. Here we show that the HIV-1 provirus activates innate immune signaling in isolated dendritic cells, macrophages, and CD4+ T cells. Immune activation requires transcription from the HIV-1 provirus and expression of CRM1-dependent, Rev-dependent, RRE-containing, unspliced HIV-1 RNA. If rev is provided in trans, all HIV-1 coding sequences are dispensable for activation except those cis-acting sequences required for replication or splicing. Our 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.

Date: 2018
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DOI: 10.1038/s41467-018-07753-2

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