Abstract
BackgroundHost cell microRNAs (miRNAs) have been shown to regulate the expression of both cellular and viral RNAs, in particular impacting both Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV). To investigate the role of miRNAs in regulating replication of the simian immunodeficiency virus (SIV) in macrophage lineage cells, we used primary macrophages to study targeting of SIV RNA by miRNAs. We examined whether specific host miRNAs directly target SIV RNA early in infection and might be induced via type I interferon pathways.ResultsmiRNA target prediction programs identified miRNA binding sites within SIV RNA. Predicted binding sites for miRs-29a, -29b, -9 and -146a were identified in the SIV Nef/U3 and R regions, and all four miRNAs decreased virus production and viral RNA expression in primary macrophages. To determine whether levels of these miRNAs were affected by SIV infection, IFNβ or TNFα treatments, miRNA RT-qPCR assays measured miRNA levels after infection or treatment of macrophages. SIV RNA levels as well as virus production was downregulated by direct targeting of the SIV Nef/U3 and R regions by four miRNAs. miRs-29a, -29b, -9 and -146a were induced in primary macrophages after SIV infection. Each of these miRNAs was regulated by innate immune signaling through TNFα and/or the type I IFN, IFNβ.ConclusionsThe effects on miRNAs caused by HIV/SIV infection are illustrated by changes in their cellular expression throughout the course of disease, and in different patient populations. Our data demonstrate that levels of primary transcripts and mature miRs-29a, -29b, -9 and -146a are modulated by SIV infection. We show that the SIV 3′ UTR contains functional miRNA response elements (MREs) for all four miRNAs. Notably, these miRNAs regulate virus production and viral RNA levels in macrophages, the primary cells infected in the CNS that drive inflammation leading to HIV-associated neurocognitive disorders. This report may aid in identification miRNAs that target viral RNAs and HIV/SIV specifically, as well as in identification of miRNAs that may be targets of new therapies to treat HIV.
Highlights
Host cell microRNAs have been shown to regulate the expression of both cellular and viral RNAs, in particular impacting both Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV)
Many miRNAs were identified that have predicted miRNA response elements (MREs) in the simian immunodeficiency virus (SIV) RNA 3′ untranslated region (UTR), and we focus here on miRs-29a, -29b, -9 and -146a, (Figure 1A and B)
All four miRNAs contain promoter binding sites for transcription factors induced during innate immune signaling. miRs-29a and -29b are predicted to contain two ISRE (STAT1/STAT2 heterodimer induced by type I IFN signaling) GAS (STAT1 homodimer activated by IFNγ signaling) binding sites in the promoter [61] and are induced in response to IFNα/β and IFNγ
Summary
Host cell microRNAs (miRNAs) have been shown to regulate the expression of both cellular and viral RNAs, in particular impacting both Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV). As a result of the development of Highly Active Antiretroviral Therapy (HAART), infected individuals are living longer, healthier lives than just two decades ago Despite this success, The type I IFN response is a major host defense against virus infection [6,7]. In our SIV macaque model of HIV central nervous system (CNS) disease, analysis of plasma, cerebrospinal fluid, basal ganglia and parietal cortex shows distinct differences in innate immune responses between the periphery and the CNS. This is exhibited by the presence of viral RNA accompanied by induction of IFNβ and IFNβinducible MxA in the CNS as early as 4 days after infection [8]. These include, but are not limited to, TRIM5α [18,19], APOBEC3G [20,21], SAMHD1 [22,23] and miRNAs [24,25]
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