Abstract
BackgroundInterferon-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.MethodsGlobal 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.ResultsmiR-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.ConclusionsThe 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.
Highlights
Induction of interferon-a (IFN-a) expression is a critical first step in the defense against a range of viral pathogens [1,2]
Our group recently published data suggesting that several host restriction factors including BST-2/tetherin and members of the tripartite motif (TRIM) and APOBEC3 families play critical roles in the interferon-mediated suppression of HIV-1 viremia in chronically-infected individuals [15,16] and in the control of HIV-1 in vivo in the absence of antiretroviral therapy (ART) [17]
We examined the effects of exogenous IFN-a treatment on PBMC miRNA profile, focusing on seven subjects before, during and after IFN-a/RBV therapy (Table S1)
Summary
Induction of interferon-a (IFN-a) expression is a critical first step in the defense against a range of viral pathogens [1,2]. A provocative recent report demonstrated that IFN-a treatment results in sustained viral suppression in the absence of antiretroviral therapy (ART) and significant reduction in the size of the HIV-1 reservoir in chronically-infected individuals [7,8]. Our group recently published data suggesting that several host restriction factors including BST-2/tetherin and members of the tripartite motif (TRIM) and APOBEC3 families play critical roles in the interferon-mediated suppression of HIV-1 viremia in chronically-infected individuals [15,16] and in the control of HIV-1 in vivo in the absence of antiretroviral therapy (ART) [17]. To inform the development of novel miRNA-based antiretroviral strategies, we investigated the effects of exogenous IFN-a 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
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