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Role of microRNA modulation in the interferon-α/ribavirin suppression of HIV-1 in vivo.

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Abdel-Mohsen Mohamed, Deng Xutao, Danesh Ali, Liegler Teri, Jacobs Evan S, Rauch Andri, Ledergerber Bruno, Norris Philip J, Günthard Huldrych F, Wong Joseph K, Pillai Satish K,
Project Swiss HIV Cohort Study (SHCS)
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Original article (peer-reviewed)

Journal PloS one
Volume (Issue) 9(10)
Page(s) 109220 - 109220
Title of proceedings PloS one
DOI 10.1371/journal.pone.0109220

Open Access

URL http://doi.org/10.1371/journal.pone.0109220
Type of Open Access Publisher (Gold Open Access)

Abstract

Interferon-α (IFN-α) treatment suppresses HIV-1 viremia and reduces the size of the HIV-1 latent reservoir. Therefore, investigation of the molecular and immunologic effects of IFN-α may provide insights that contribute to the development of novel prophylactic, therapeutic and curative strategies for HIV-1 infection. In this study, we hypothesized that microRNAs (miRNAs) contribute to the IFN-α-mediated suppression of HIV-1. To inform the development of novel miRNA-based antiretroviral strategies, we investigated the effects of exogenous IFN-α treatment on global miRNA expression profile, HIV-1 viremia, and potential regulatory networks between miRNAs and cell-intrinsic anti-HIV-1 host factors in vivo. Global miRNA expression was examined in longitudinal PBMC samples obtained from seven HIV/HCV-coinfected, antiretroviral therapy-naïve individuals before, during, and after pegylated interferon-α/ribavirin therapy (IFN-α/RBV). We implemented novel hybrid computational-empirical approaches to characterize regulatory networks between miRNAs and anti-HIV-1 host restriction factors. miR-422a was the only miRNA significantly modulated by IFN-α/RBV in vivo (p<0.0001, paired t test; FDR<0.037). Our interactome mapping revealed extensive regulatory involvement of miR-422a in p53-dependent apoptotic and pyroptotic pathways. Based on sequence homology and inverse expression relationships, 29 unique miRNAs may regulate anti-HIV-1 restriction factor expression in vivo. The specific reduction of miR-422a is associated with exogenous IFN-α treatment, and likely contributes to the IFN-α suppression of HIV-1 through the enhancement of anti-HIV-1 restriction factor expression and regulation of genes involved in programmed cell death. Moreover, our regulatory network analysis presents additional candidate miRNAs that may be targeted to enhance anti-HIV-1 restriction factor expression in vivo.
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