- Open Access
RNAi in the regulation of mammalian viral infections
© Jeang; licensee BioMed Central Ltd. 2012
- Received: 10 April 2012
- Accepted: 22 June 2012
- Published: 26 June 2012
Although RNA interference (RNAi) is known to play an important part in defense against viruses of invertebrates, its contribution to mammalian anti-viral defense has been a matter of dispute. This is surprising because all components of the RNAi machinery necessary for robust RNAi-mediated restriction of viruses are conserved in mammals, and the introduction of synthetic small interfering RNAs (siRNAs) into cells efficiently silences the replication of viruses that contain siRNA complementary sequences in those cells. Here, I discuss the reasons for the dispute, and review the evidence that RNAi is a part of the physiological defense of mammalian cells against viral infections.
- Human Papilloma Virus
- RISC Complex
- PIWI Protein
- Invertebrate Cell
- Cellular miRNAs
RNA interference (RNAi) is a process in which small non-coding RNAs (of endogenous or exogenous origin) are incorporated into a multi-protein RNA-induced silencing complex (RISC) in cells to silence the expression of a sequence-homologous target RNA . Three major types of small non-coding RNAs function as RNAi: the piRNAs (PIWI-interacting RNAs), miRNAs (microRNAs), and siRNAs (small interfering RNAs). piRNAs and miRNAs are endogenous, small non-coding RNAs transcribed from cellular loci and then processed to generate fragments that engage with the downstream silencing machinery. Until recently, siRNAs were thought to be exclusively processed from the exogenous RNA of pathogens (for example, viruses) that infect the cell, but that view changed with the discovery of abundantly expressed endogenous siRNAs (endo-siRNAs) in animal cells [2, 3]. Currently, mammals are known to have hundreds of thousands of different piRNAs, produced from gene clusters of repetitive elements, and more than 1,000 different miRNAs; the number of endo-siRNAs still needs to be fully clarified.
One of the earliest descriptions of RNAi was in Caenorhabditis elegans. Early on, it was found that mutations affecting RNAi function in C. elegans and Drosophila melanogaster produced apparently normal organisms, but that these mutations increased the susceptibility of mutated animals to infection by viruses [5, 6]. These findings suggested an evolutionary role for RNAi in the defense of cells against pathogenic viral infections. Indeed, this rationale is consistent with the role of RNAi in post-transcriptional gene silencing of plant viruses  and with the conservation of an RNAi-like antiviral defense mechanism using small CRISPR (clusters of regularly interspaced short palindromic repeats) RNAs in prokaryotes . The need for conservation of an analogous antiviral system in vertebrates, however, has been questioned on the grounds of their advanced adaptive immunity to viral (and non-viral) pathogens and on the emergence of an interferon-based defense mechanism. Silencing mechanisms that depend on RNAi are, however, already known to operate in vertebrates to protect the germline DNA from transposons and endogenous retroviruses; and as discussed below, they appear also to operate in somatic cells.
Non-virologists are often surprised to learn that nearly 50% of the human genome is made up of virus-like transposable elements (TEs) , which are composed mostly of retrotransposons replicated through reverse transcription, and DNA transposons propagated through a cut-and-paste mechanism. Included among the TEs in the mouse and human genomes are distinctly recognizable endogenous retroviruses (ERVs; integrated retrovirus sequences that have entered the germline), with 5 to 8% of human DNA estimated to consist of human endogenous retrovirus (HERV) elements that segregate into 26 phylogenetically distinct retroviral lineages . These ERVs are likely to be fossilized remnants of anciently endogenized virus infections. While active human ERVs are rare , human non-ERV TEs (for example, short interspersed elements - SINES - and long interspersed elements - LINES) remain active for transposition, accounting for 1 new insertion every 100 to 200 human births or roughly 1 in every 1,000 human genetic mutations . By contrast, mouse ERVs are numerous and highly active and cause approximately 10% of spontaneous mutations in inbred mice .
Active replication of ERVs and virus-like elements needs to be suppressed in the germ line because they cause novel deleterious germline mutations. In mouse germ cells, piRNA-mediated silencing has been shown to be important for repressing TE activity . However, ERV and retrotransposon activities are not limited to the germline; they also occur in somatic cells where they can induce disease, in particular ERV- and retrotransposition-associated cancers [15, 16]. This raises the question of whether mechanisms also exist to protect somatic tissues. There is evidence for two such mechanisms. First, somatic cell endo-siRNAs, as recently described, may act to control ERV and TE activity . Second, emerging data have unexpectedly revealed that piRNAs are not confined to germline cells, but are also abundant in the somatic tissues of fruitfly, mouse, and rhesus macaques , in the neurons of Aplysia , and in a human T cell line . PIWI mRNA and MIWI protein have also been detected in macaque and mouse somatic tissues . If these new discoveries are confirmed, then ERV/TE-suppression in somatic cells may be mediated by piRNA-RISC.
There is also direct evidence supporting a role for RNAi in regulating viral infections in mammalian cells. As in the early studies that showed RNAi pathway mutations in C. elegans and D. melanogaster increased these organisms' susceptibility to infection by viruses [5, 6], mutations in or perturbation of RNAi pathway components in mouse , monkey cells  or human cells [22, 23] increase the replication of vesicular stomatitis virus (VSV), influenza A virus, and human immunodeficiency virus (HIV-1), respectively.
The above arguments apply to retroviruses and herpes viruses, which have been extensively studied for RNAi generation. What remains unaddressed is the processing of the many plus-sense, minus-sense, and human dsRNA viruses. These viruses present fully dsRNA substrates as part of their genomes or as replication intermediates. To date, they have not been extensively investigated for the biogenesis of viral non-coding RNAs, and future findings from these viruses could yield important insights.
Several aspects of the RNAi-virus-host cell interaction also merit closer scrutiny. One issue is whether the expression of endo-siRNAs in mammals is similar between germline tissues and somatic tissues. The data for somatic tissues are currently incomplete. The emerging finding that piRNAs are present in both germ and somatic cells raises the possibility that endo-siRNAs conform to an analogous pattern.
A second issue is the dynamic strike-counterstrike interplay between cells in which RNAi serves to combat viruses and viruses evade RNAi to successfully replicate in cells . One view is that efficiently replicating viruses must encode RNAi suppressors. Indeed, while many mammalian viruses do apparently have RNAi suppressor moieties , an RNAi suppressor function is only one of several means (for example, shielding of the virus genome from RNAi, sequence changes in the viral genome to evade RNAi, virus modulation of cellular miRNA expression, and virus adaptation to cellular RNAi)  at the virus' disposal to skirt cellular RNAi restriction. Indeed, shielding of the viral RNA genome from RNAi , changes in viral sequences to evade RNAi , and virus-modulation of cellular miRNA-expression [48–50] have all been reported for HIV-1. Viruses such as HIV-1 that are highly mutable may evade RNAi efficiently through target sequence changes; these viruses do not need a strong RNAi suppressor [37, 51, 52], if at all . On the other hand, less mutable viruses may require strong RNAi suppressors to mitigate RNAi restriction in order to replicate optimally.
A final issue is the increasingly convincing new evidence for the existence of natural antisense transcripts in human T-lymphotropic virus (HTLV)-1 and HIV-1 [54–58]. Inside cells, these antisense viral RNAs can, in principle, form long RNA duplexes with their complementary sense transcripts. The fate of these dsRNAs and what new functions they may provide promise to keep virologists busy for the next several years.
I thank Christine Kozak, Dong-yan Jin, Andrew Dayton, and Laurent Houzet for advice on this writing and Lauren Lee for preparation of the figures. Work in my laboratory is supported in part by intramural funds from the NIAID and by the IATAP program from the office of the director, NIH. The opinions in this article represent my personal views and do not necessarily reflect the views of my employer, the NIH.
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