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: Mohamed Abdel-Mohsen, Xutao Deng, Ali Danesh, Teri Liegler, Evan S Jacobs, Andri Rauch, Bruno Ledergerber, Philip J Norris, Huldrych F Günthard, Joseph K Wong, Satish K Pillai
• Journal: PloS one (PLoS One) Vol. 9 Issue 10 Pg. e109220 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 25275557 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Interferon-alpha
• MicroRNAs
• Ribavirin

Topics

• Gene Expression Profiling
• HIV Infections (complications, drug therapy)
• HIV-1 (drug effects)
• Hepatitis C (complications, drug therapy)
• Humans
• Interferon-alpha (pharmacology, therapeutic use)
• MicroRNAs (genetics, metabolism)
• Ribavirin (pharmacology, therapeutic use)