title: Role of microRNA modulation in the interferon-α/ribavirin suppression of HIV-1 in vivo.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California, United States of America; Blood Systems Research Institute, San Francisco, California, United States of America.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abdel-Mohsen
authors.affiliation: Blood Systems Research Institute, San Francisco, California, United States of America.
authors.forename: Xutao
authors.initials: X
authors.lastname: Deng
authors.affiliation: Blood Systems Research Institute, San Francisco, California, United States of America.
authors.forename: Ali
authors.initials: A
authors.lastname: Danesh
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Teri
authors.initials: T
authors.lastname: Liegler
authors.affiliation: Blood Systems Research Institute, San Francisco, California, United States of America.
authors.forename: Evan S
authors.initials: ES
authors.lastname: Jacobs
authors.affiliation: Department of Infectious Diseases, Bern University Hospital and University of Bern, Bern, Switzerland.
authors.forename: Andri
authors.initials: A
authors.lastname: Rauch
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Ledergerber
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California, United States of America; Blood Systems Research Institute, San Francisco, California, United States of America; Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Norris
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Huldrych F
authors.initials: HF
authors.lastname: Günthard
authors.affiliation: Department of Medicine, San Francisco Veterans Affairs Medical Center, San Francisco, California, United States of America.
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Wong
authors.affiliation: Blood Systems Research Institute, San Francisco, California, United States of America; Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Satish K
authors.initials: SK
authors.lastname: Pillai
mesh_terms: D020869:Gene Expression Profiling; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects*; D006526:Hepatitis C / Q000150:complications / Q000188:drug therapy; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology* / Q000627:therapeutic use; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D012254:Ribavirin / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D016898:Interferon-alpha; D035683:MicroRNAs; D012254:Ribavirin