Abstract
PurposeTo determine whether HIV-1 produces microRNAs and elucidate whether these miRNAs can induce inflammatory response in macrophages (independent of the conventional miRNA function in RNA interference) leading to chronic immune activation.MethodsUsing sensitive quantitative Real Time RT-PCR and sequencing, we detected novel HIV-derived miRNAs in the sera of HIV+ persons, and associated with exosomes. Release of TNFα by macrophages challenged with HIV miRNAs was measured by ELISA.ResultsHIV infection of primary alveolar macrophages produced elevated levels of viral microRNAs vmiR88, vmiR99 and vmiR-TAR in cell extracts and in exosome preparations from conditioned medium. Furthermore, these miRNAs were also detected in exosome fraction of sera from HIV-infected persons. Importantly, vmiR88 and vmiR99 (but not vmiR-TAR) stimulated human macrophage TNFα release, which is dependent on macrophage TLR8 expression. These data support a potential role for HIV-derived vmiRNAs released from infected macrophages as contributing to chronic immune activation in HIV-infected persons, and may represent a novel therapeutic target to limit AIDS pathogenesis.ConclusionNovel HIV vmiR88 and vmiR99 are present in the systemic circulation of HIV+ persons and could exhibit biological function (independent of gene silencing) as ligands for TLR8 signaling that promote macrophage TNFα release, and may contribute to chronic immune activation. Targeting novel HIV-derived miRNAs may represent a therapeutic strategy to limit chronic immune activation and AIDS progression.
Highlights
Persons infected with HIV-1 exhibit a state of chronic immune activation, characterized by persistent and aberrant activation of immune cells, and increased tissue levels of pro-inflammatory mediators such as TNFa [1], that contributes to AIDS pathogenesis and may persist despite effective combined antiretroviral treatment [2]
In the current study focusing on human macrophages, we report on two novel HIV-derived miRNA that are released by HIV-infected macrophages and directly stimulate recipient macrophage early TNFa release that is dependent in part on macrophage Toll-like receptor 8 (TLR8)
We previously reported that HIV ssRNA40 induced macrophage TNFa release via TLR8-mediated signaling and chromatin remodeling, and ssRNA40 biological activity was dependent on relative high guanosine + uridine (G+U) content [8]
Summary
Persons infected with HIV-1 exhibit a state of chronic immune activation, characterized by persistent and aberrant activation of immune cells, and increased tissue levels of pro-inflammatory mediators such as TNFa [1], that contributes to AIDS pathogenesis and may persist despite effective combined antiretroviral treatment (cART) [2]. Chronic immune activation may play a role in the pathogenesis of AIDS, since natural hosts of simian immunodeficiency virus (SIV) such as sooty mangabeys fail to develop immunodeficiency and AIDS despite high levels of viral replication, while exhibiting surprisingly low levels of immune activation during the chronic stage of infection [5]. SIV infection of rhesus macaques and other non-natural hosts results in high levels of systemic immune activation, CD4+ T-cell depletion and rapid progression to AIDS [6]. Viral miRNAs from HIV have been described such as HIV vmiR-TAR [12,13,14,15], that may influence host cell function through RNAi function [16], but whether other biologically active HIV-derived miRNAs that can directly stimulate bystander or recipient host cells has not been established
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