Trends in Immunology
OpinionVirus-specific host miRNAs: antiviral defenses or promoters of persistent infection?
Section snippets
RNA silencing and immunity
RNA silencing (Figure 1) is a widely conserved mechanism of post-transcriptional gene regulation. RNA interference (RNAi) is also an integral part of the antiviral defense in plants and invertebrates, which can process virus-derived long double stranded RNAs (dsRNA) into small interfering RNAs (siRNAs), amplify siRNAs by RNA dependent RNA polymerases (RDRP) and induce systemic RNAi [1]. The presence of a viral counter-defense in the form of viral suppressors of RNA silencing (VSRs) in numerous
Host miRNAs and chronic HCV infection
HCV is unique among the hepatitis viruses in its striking predilection for inducing chronic infection, with more than three-quarters of HCV infections resulting in chronic hepatitis [8]. The impaired innate immune responses and the ability of HCV to rapidly evolve under constant immune pressure might both contribute to viral persistence [9]. Like other RNA viruses, HCV encodes its own RNA polymerase that lacks a proofreading activity. As a result, replication of HCV is highly error prone and
Host miRNAs and other persistent virus infections
Co-option of host miRNAs by viruses to suppress their own gene expression could also contribute to persistent infection of other viruses. Retroviruses such as human immunodeficiency virus (HIV) are maintained in latent reservoirs in the host throughout the course of infection [17]. By shutting off replication, the latent reservoir of viruses can escape the immune system until future reactivation. HIV replication is suppressed by cellular miRNAs such as miR-28, miR-125b, miR-223 and miR-382 in
Virus-host miRNA interactions in dead-end hosts
Two widely expressed miRNAs, miR-24 and miR-93, have been shown to target vesicular stomatitis virus (VSV) and protect mice against VSV infection [24]. VSV infects both insects and animals in the wild because of the broad tropism of the coat protein. Infected black flies can horizontally transmit VSV to uninfected flies when they co-feed on the same host [25]. Therefore, it has been suggested that livestock are just indicator hosts of a passive insect reservoir of VSV [26]. Although laboratory
Conclusions
We propose that IFN-inducible miRNAs are among the host molecules that HCV co-opts to suppress its own replication to avoid sterilizing immunity and establish chronic infection. By the same notion, we speculate that other rapidly evolving viruses, such as HIV and PFV, have also evolved mechanisms to utilize host miRNAs for immune evasion and persistent infection. The proposed host miRNA-dependent mechanism probably acts in concert with other host and viral factors, such as immune exhaustion and
Acknowledgements
We would like to thank Dr. Herman N. Eisen for a critical review of the manuscript, Dr. Patrick Stern, Dr. Ramya Rajagopalan and Dr. Ching-Hung Shen for helpful discussions. This work was supported in part by grants from National Institutes of Health (AI40146 and AI69208) and Singapore-MIT Alliance in Research and Technology (SMART) to J.C.
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These authors contributed equally to this work.