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.
Highlights
HIV-1-infected people who take drugs that suppress viremia to undetectable levels are protected from developing AIDS
To increase the efficiency of provirus establishment, vectors were pseudotyped with the vesicular stomatitis virus glycoprotein (VSV G) and delivered concurrently with virus-like particles (VLPs) bearing SIVMAC251 Vpx (Fig. 1b)[16,32]
Expression of the unspliced transcript requires specialized viral and cellular machinery, HIV-1 Rev and CRM145, in order to escape from processing by the spliceosome
Summary
HIV-1-infected people who take drugs that suppress viremia to undetectable levels are protected from developing AIDS. There are currently over 40 antiretroviral drug formulations that block essential steps in the HIV-1 replication cycle, including reverse transcription, integration, and proteolytic processing of the viral polyproteins[1,2]. These treatments are effective at reducing viremia, HIV-1 establishes proviruses in long-lived CD4+ memory T cells, and perhaps other cell types[3,4,5], that preclude elimination of the virus even after years of continuous antiviral therapy[6]. The results show that high-level activation of innate immune gene expression in transduced cells requires integration, as well as transcription from the provirus. The observations reported here demonstrate that the innate immune system detects HIV-1’s unique modes of RNA processing and suggest that inhibitors of HIV-1 transcription or HIV-1 RNA metabolism would be beneficial additions to current retroviral therapy
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