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Published in final edited form as: Virus Res. 2015 Oct 23;212:1–11. doi: 10.1016/j.virusres.2015.10.002

Long noncoding RNAs in viral infections

Puri Fortes 1,*, Kevin Morris 2,3
PMCID: PMC4744516  NIHMSID: NIHMS732475  PMID: 26454188

Abstract

Viral infections induce strong modifications in the cell transcriptome. Among the RNAs whose expression is altered by infection are long noncoding RNAs (lncRNAs). LncRNAs are transcripts with potential to function as RNA molecules. Infected cells may express viral lncRNAs, cellular lncRNAs and chimeric lncRNAs formed by viral and cellular sequences. Some viruses express viral lncRNAs whose function is essential for viral viability. They are transcribed by polymerase II or III and some of them can be processed by unique maturation steps performed by host cell machineries. Some viral lncRNAs control transcription, stability or translation of cellular and viral genes. Surprisingly, similar functions can be exerted by cellular lncRNAs induced by infection. Expression of cellular lncRNAs may be altered in response to viral replication or viral protein expression. However, many cellular lncRNAs respond to the antiviral pathways induced by infection. In fact, many lncRNAs function as positive or negative regulators of the innate antiviral response. Our current knowledge about the identity and function of lncRNAs in infected cells is very limited. However, research into this field has already helped in the identification of novel cellular pathways and may help in the development of therapeutic tools for the treatment of viral infections, autoimmune diseases, neurological disorders and cancer.

Keywords: lncRNAs, proviral, antiviral, IFN response, lncRNA processing, transcription regulation, RNA interference

1. Long non coding RNAs

The firsts transcriptome analyses, carried out a decade ago, led to the unexpected discovery that while the majority of the genome is transcribed, only ~2% of the genome is transcribed into mRNAs that are then translated into proteins. While most investigation to date has focused on the study protein functionality in health and disease, it is now apparent that the majority of the genome is transcribed as noncoding RNAs (Cawley et al., 2004; ENCODE Project Consortium et al., 2007). Among the noncoding genome, long noncoding RNAs (lncRNAs) are a particularly rich category. Some estimates suggest that the human genome contains more than 90,000 genes and approximately 60,000 of them are lncRNAs, while other estimates suggest that the number of lncRNA genes could reach closer to 200,000 (Iyer et al., 2015). Notably the number of lncRNAs scales with developmental complexity, with primates exhibiting the largest number of lncRNA genes followed by mouse and scaling down accordingly to bacteria (Ulitsky et al., 2011). The function of most of these non-coding transcripts remains largely unknown (Cech and Steitz, 2014). Indeed great efforts are being made to identify the complete collection of lncRNA genes in different species and assign to them functional categories.

LncRNAs are generally classified as transcripts longer than 200 nucleotides with no identifiable protein coding capacity and with potential to function predominantly as RNA molecules (Cech and Steitz, 2014). LncRNAs are generally thought to be transcribed by RNA polymerase II, have one or more introns eliminated by splicing, and some appear to be polyadenylated at their 3′ end (Derrien et al., 2012). In essence lncRNAs are generally similar to mRNAs (Garitano et al., 2013). However, compared to mRNAs, lncRNAs are preferentially nuclear, more tissue specific, poorly expressed and poorly conserved (Djebali et al., 2012). This may be one reason as to why these transcripts, until recently, have gone unnoticed. Once transcribed, some lncRNAs form a secondary/tertiary structure and interact with proteins, DNA or other RNAs to fulfil regulatory functions (Cech and Steitz, 2014). Some lncRNAs act in trans, away from their site of transcription, while other act in cis, controlling the expression of neighbouring genes (Gupta et al., 2010). Several examples exist of lncRNAs that control gene expression by guiding chromatin remodelers, inducing DNA bending, regulating transcription, splicing, translation, or RNA stability (Gupta et al., 2010; Khalil et al., 2009; Tsai et al., 2010; Yao et al., 2010; Feng et al., 2006; Tripathi et al., 2010; Carrieri et al., 2012; Cesana et al., 2011; Yoon et al., 2012). Other lncRNAs have been described to serve as scaffolds of subnuclear structures or to control protein transport or post-translational modifications (Mao et al., 2011; Willingham et al., 2005; Wang et al., 2014). The function of several lncRNAs has been shown to be essential in cell homeostasis, growth and differentiation. Further, several lncRNAs have been described as playing relevant roles in viral infection and in the antiviral response (reviewed in this Special Issue).

2. Protein-modulated control of the antiviral response

The antiviral response is induced in response to viral infection by detection of pathogen-associated molecular patterns (PAMPs) (Schneider et al., 2014). PAMPs can be detected by canonical sensors, such as the retinoic acid-inducible gene I (RIG-I) or toll-like receptors (TLRs) or by non-canonical factors such as the protein kinase R (PKR) (Andrejeva et al., 2004; Kang et al., 2002; Yoneyama et al., 2004; Alexopoulou et al., 2001; Diebold et al., 2004; Arnaud et al., 2010; Arnaud et al., 2011). Most TLRs signal through the myeloid differentiation primary response gene 88 (MyD88) and the tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6) to activate the nuclear factor-κB (NF-κB). The endosome-bound TLR3 activates the innate immune response through the toll-IL-1 receptor domain-containing adaptor inducing interferon (TRIF) (Li et al., 2012) and RIG-I requires the E3 ubiquitin ligase TRIM25 (Gack et al., 2007), which facilitates the interaction of RIG-I with the mitochondrial antiviral-signaling protein (MAVS) (Fig. 1). When MAVS or TRIF are triggered, they lead to the activation of the Interferon (IFN) regulatory factor (IRF) 3 and NF-κB (Gack et al., 2007; Loo and Gale, 2011). Together, IRF3 and NF-κB induce transcription of type I IFN. Further, IRF3 and NF-κB on their own can induce transcription of IFN regulated genes (ISGs) and proinflammatory cytokines, respectively.

Fig. 1. Several lncRNAs regulate the antiviral pathway.

Fig. 1

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See the text for details. Proteins involved in the antiviral response are in blue. LncRNAs are in red. Ubiquitin is in yellow. P denotes phosphorylation. Activation is shown with an arrow. Inhibition is depicted with an interrupted line.

Secreted type I IFN (IFNα, IFNβ and others) binds to IFN receptors and activates JAK/STAT (Janus-activated kinase/signal transducer and activator of transcription) signaling (Ivashkiv and Donlin, 2014). STAT1 and 2 coupled to IRF9 activate the transcription of ISGs which function to induce an antiviral state in the cell. STAT1, STAT2, IRF1, 3, 7, 9 or OAS (2′-5′ oligoadenylate synthase) are ISGs that work to increase cell sensitivity to PAMPs and reinforce IFN signaling. Other ISGs block viral infection by affecting several steps of the viral cell cycle, including viral entry and release, and RNA replication, translation and stability. Surprisingly, some ISGs function as negative regulators of the IFN response (Schneider et al., 2014). These regulators are essential to control the response and to help the cell return to homeostasis.

Among the regulators of the IFN pathway, factors involved in protein ubiquitination seem to have special relevance (reviewed in Davis and Gack, 2015). Ubiquitin is a polypeptide that can be covalently bound to a protein substrate (reviewed in Clague et al., 2015). Ubiquitin binding requires an E1 activating enzyme, an E2 conjugating enzyme and an E3 ligase that selects the target. Ubiquitin release from the target requires a deubiquitinating enzyme (DUB). Many polyubiquitinated proteins are targeted to the proteasome for degradation. However, ubiquitination can also induce endosomal and autophagosomal degradation or alter protein functionality. Several sensors and mediators of IFN synthesis and signaling modify their stability or functionality by ubiquitination. These include MyD88, TRIF or nuclear IRF3, degraded after the action of several E3 ligases, whose increase reduces IFN synthesis (Xue et al., 2012; Yang et al., 2013a; Wang et al., 2015). In contrast, USP13 (Ubiquitin Specific Peptidase 13) is a DUB that deubiquitinates STAT1 to avoid degradation and potentiate IFN signaling (Yeh et al., 2013). More complex is the ubiquitin-regulation of RIG-I. RIG-I can be ubiquitinated and degraded by RNF125 (Ring Finger Protein 125) and deubiquitinated and stabilized by USP4 (Wang et al., 2013; Luo et al., 2013). Further, RIG-I can be ubiquitinated and activated by TRIM25, which, in turn, can be ubiquitinated and degraded by LUBAC (linear ubiquitin chain assembly complex) and deubiquitinated and stabilized by USP15 (Davis and Gack, 2015) (Fig. 1). Interestingly, many ubiquitin related proteins are induced by IFN to enhance (TRIM25) or to block (TRIM13 or 21) the IFN response (Zhang et al., 2013a; Narayan et al., 2014). Similarly, many viruses express ubiquitin ligases or DUBs to alter ubiquitin regulation and favor replication (Kwon and Ahn, 2013) or express proteins that block the action of several ubiquitin enzymes that lead to the activation of the IFN pathway (Rajsbaum et al., 2012).

Similar regulation is exerted by ubiquitin-like proteins such as the small ubiquitin-like modifier (SUMO) or ISG15. IFN induces SUMOylation of STAT-1, which leads to decreased STAT1 phosphorylation and signaling (Maarifi et al., 2015). ISG15 and the complete ISGylation machinery are induced by IFN and other viral sensors to play proviral and antiviral roles (Arnaud et al., 2011). As the ISGylation machinery acts cotranscriptionally, ISG15 conjugation occurs preferentially in viral proteins and cellular antiviral factors whose translation is increased after infection (Durfee et al., 2010). ISGylation of viral proteins affects their functionality and therefore, exerts and antiviral function (Zhao et al., 2013). ISGylation of IRF3 and RIG-I affects their ubiquitination, leading to an increased stability of IRF3 and decreased functionality of RIG-I. This leads to decreased IFN production and increased viral replication (Shi et al., 2010; Broering et al., 2010; Kim et al., 2008). In line with this proviral role, free ISG15 also stabilizes the deISGylase USP18, which binds IFNA2R (IFN alpha 2 receptor) and blocks IFN signaling (Malakhova et al., 2003; Malakhova et al., 2006; Zhang et al., 2015).

A tight regulation of functionality and stability by ubiquitin and ubiquitin-like proteins is only one of the constraints that host and viral proteins suffer after infection. Further, protein translation is also blocked, mainly, by PKR activation. PKR is an IFN-induced kinase with several functions (reviewed in Dabo and Meurs, 2012). One of the key functions of PKR after activation is the phosphorylation of eukaryotic translation initiation factor eIF2a, a subunit of the eIF2 factor (Fig. 1). eIF2 together with GTP and Met-tRNA, forms a ternary complex required to position the initiating Met-tRNA codon and start translation. GTP hydrolysis allows recycling of the complex. Phosphorylation of eIF2a prevents the regeneration of GTP in the ternary complex and then blocks cap-dependent translation.

3. Viruses and lncRNAs

Viruses have developed several strategies to fight the antiviral immune system and to increase the efficacy of replication (reviewed in Horner and Gale, 2013). Recent studies show that some of these strategies function through lncRNA molecules. This is not surprising because:

  1. Viruses adopt similar molecular mechanisms than those that function in the host cell. In this way the virus can employ host cell machineries. Host cells express many functional lncRNAs, making likely that viruses also express them.

  2. Viruses are under strong selective pressure from the cell. Molecules that constrain viral replication should tend to be selected more easily. It should be easier for RNA viruses, which employ error-prone polymerases, to utilize ncRNAs to elude selective pressures exerted by the cell on the virus. This is because lncRNAs appear to tolerate mutations better than coding genes (Ulitsky et al., 2011; Ponjavic et al., 2007). As such, one would predict that it is more likely that novel viral protective and/or viral repressive cellular functions will develop from lncRNAs.

  3. Effectiveness of molecules that boost replication should be enhanced when they are invisible to the cellular antiviral sensors or the acquired immune system. This is an advantage of lncRNAs compared to protein factors and PAMPs.

  4. As indicated above, the cell responds to infection with upregulation of machineries that affect the cellular proteome. Translation of new proteins is blocked by PKR activation and pre-existing proteins are affected in their stability and functionality by the binding of ubiquitin and ubiquitin-like proteins. LncRNAs should be immune to this protein-hostile environment.

These are reasons why viral lncRNAs are expected to be generated, function to improve viral viability and resist the cellular antiviral atmosphere. Noticeable, lncRNAs employed by the virus to enhance replication could be cellular lncRNAs whose expression is induced by the virus in the infected cell. Similarly, the infected cell has also evolved to express cellular lncRNAs that counteract viral infection.

3. 1. lncRNAs in infected cells

Transcriptome analysis of cells infected with different viruses has led to the identification of viral lncRNAs and cellular lncRNAs whose expression is altered after infection.

3.1.1. Cell lncRNAs altered by infection

When transcriptomes of infected and control cells are contrasted, there are distinct changes in particular lncRNAs. Expression of some of these lncRNAs is altered in response to the expression of viral proteins. For example the expression of X protein (HBx) from Hepatitis B virus (HBV) in cultured cells or transgenic mice, leads to the downregulation of the tumor suppressor lncRNA DREH (down-regulated expression by HBx) (Huang et al., 2013; Moyo et al., 2015). Similarly, expression of Nef at early times post-infection with human immunodeficiency virus (HIV) reduces expression of the lncRNA NRON (noncoding repressor of nuclear factor of T cells (NFAT)) (Imam et al., 2015; Lazar et al., 2015). As NRON is a repressor of NFAT, decreased levels of NRON allow NFAT-mediated transcription of HIV genes at early times post-infection. Interestingly, expression of Vpu protein at late times post-infection with HIV increases NRON expression. This results in decreased NFAT functionality and decreased transcription of HIV genes at late times, prior to viral release and apoptosis. Thus, levels of NRON change during HIV infection to allow transcription regulation. These results also teach us that a proper evaluation of the levels of lncRNAs in infected cells should be performed at different times post-infection.

Expression of cellular lncRNAs can also be altered in response to the antiviral response induced by infection. Activation of canonical or non-canonical PAMP sensors, or treatment with IFN or TNFα (which induces transcription by NF-κB) leads to changes in the expression of many lncRNAs (reviewed in Valadkhan and Gunawardane, 2015; Carpenter, 2015; Aune and Spurlock, 2015). Similar to the induction pattern observed for coding genes, most lncRNAs appear upregulated by the treatment. However, 80% of the lncRNAs whose expression is altered after treatment of THP1 cells with a TLR2 agonist were downregulated (Li et al., 2014). Similarly, treatment of primary liver cells or the liver HuH7 cell line with IFN also resulted in the downregulation of many lncRNAs while most altered coding genes were upregulated (Kambara et al., 2014; Carnero et al., 2014; Barriocanal et al., 2015). While the function of these downregulated lncRNAs is unknown, these results suggest that IFN-regulated lncRNA genes could play different regulatory roles than IFN-induced coding genes in the control of the antiviral response.

Interestingly, the function of several lncRNAs whose expression is altered during the antiviral response has been described. As expected, most seem to regulate inflammation or antiviral gene expression by several mechanisms. Some are inducers, such as NEAT1 (nuclear enriched abundant transcript 1), which increases IL8 (interleukin 8) by sequestering the IL8-inhibitor SFPQ (splicing factor proline/glutamine rich) in paraspeckles (see below) (Imamura et al., 2014) (Fig. 1). Many are negative regulators, such as lincR-COX2 (cyclooxygenase 2), Lethe, IL7R (interleukin 7 receptor), NRAV (negative regulator of antiviral response) or NRIR (negative regulator of IFN response) (see below) (Carpenter et al., 2013; Rapicavoli et al., 2013; Cui et al., 2014; Kambara et al., 2014; Ouyang et al., 2014). Considering the small number of infection-related lncRNAs studied to date and the relatively high proportion that function as negative regulators it is tempting to speculate that lncRNAs may play a key role in the silencing of the inflammatory or the IFN pathway (Fig. 1).

3.1.2. Viral lncRNAs

The existence of viral noncoding RNAs has been known for years (Mathews, 1975; Marx, 1972). In fact, viroids were first described in 1971. Viroids and some virusoids are plant pathogens whose genome is a lncRNA, as it lacks any protein coding capacity (reviewed in Gago-Zachert, 2015; Shimura and Masuta, 2015). Viroid genomes are small 246–401 nucleotide, circular, single-stranded RNA molecules capable of autonomous replication. Viroids have been considered living relics of the hypothetical RNA world (Flores et al., 2014). As they do not encode viral proteins, the genome is transmitted by tools used to process plants for agricultural purposes. Contamination is facilitated by the high stability of the viroid genome. The genome remains infectious for long periods in dry tissue or on dry surfaces as the viroids are resistant to heat and many antiviral chemicals. Inactivation is achieved with hypochlorite and a non-rigorous cleaning of the tools causes plant contaminations and huge economic problems. Some viroids are transmitted by aphids or transferred from plant to plant by leaf contact.

The expression of noncoding RNAs from animal viruses has also been described decades ago. Some of them are very abundant, such as VA (virus-associated) RNAs from adenovirus, EBERs (Epstein-Barr virus (EBV)-encoded small RNA) from EBV or PAN (polyadenylated nuclear) RNA from Kaposi’s sarcoma-associated herpesvirus (KSHV) (reviewed in Vachon and Conn, 2015; Iwakiri, 2015; Conrad, 2016). Viral non-coding RNAs are transcribed from polymerase III (VA RNAs, EBERs) or polymerase II promoters (PAN RNA) and some can be polyadenylated (PAN RNA). Then, some accumulate preferentially in the nucleus (PAN RNA, EBERs) or in the cytoplasm (VA RNAs) of infected cells. Interestingly, some viral lncRNAs are processed by unique maturation steps performed by host cell machineries. This is the case of subgenomic flavivirus RNAs (sfRNAs) or the LAT (latency-associated transcript) from Herpes simplex virus type 1 (HSV-1).

Flavivirus genomic RNA can be degraded by the 5′ to 3′ exonuclease Xrn1. While processing, Xrn1 stalls on secondary structures located towards the 3′ end and creates degradation intermediates named sfRNAs or Xrn1-resistant RNAs (xrRNAs) (reviewed in Charley and Wilusz, 2015). This is very rare, as well-studied RNAs with strong secondary or tertiary structures are not resistant to degradation by Xrn1. Instead, flavivirus RNAs have developed a special structure to stop Xrn1 processing and accumulate to high levels. The resulting sfRNAs from arthropod-borne flaviviruses are noncoding, 300–500 nucleotides long and contain the 3′-end of the genomic RNA. Recently, it has been described that few nucleotides from the 5′ end of hepatitis C virus (HCV) genomic RNA can also be degraded by Xrn1. In this case the enzyme stalls in the IRES sequence and xrRNAs are generated (Moon et al., 2015). Whether these subgenomic HCV RNAs are non-coding transcripts is currently unknown.

During latency, HSV-1 produces only the capped, spliced and polyadenylated LAT (reviewed in Tycowski et al., 2015). Surprisingly, the spliced exon RNA is hard to detect, as it is processed further to generate several miRNAs, while the lariat with intronic sequences is very stable (Kang et al., 2006). Intron stability seems related with a secondary structure that selects a non-consensus branch site sequence for splicing (using guanosine instead of adenosine) (Mukerjee et al., 2004). Other stable intronic sequence RNAs (sisRNAs) have been recently identify in eukaryotes (Hesselberth, 2013).

Finally, it should be highlighted that, similar to coding transcripts, expression of viral lncRNAs may be tightly regulated. Some viral lncRNAs, such as LAT, are only expressed in the latent phase, while others in the lytic phase. This is the case of PAN RNA, whose high levels of expression in the lytic phase are due to increased transcription and, primarily, to several molecular mechanisms that work together or independently to result in PAN RNA stability (reviewed in Conrad, 2015).

3.1.3. Chimeric lncRNAs

The study of HBV-associated hepatocellular carcinomas (HCC) led to the identification of transcripts that result from fusions between human and viral sequences (Lau et al., 2014; reviewed in Moyo et al., 2015). This is not surprising as HBV genome can integrate into the host genome. Integration occurs preferentially within repetitive sequences such as long interspersed nuclear elements (LINEs). Unexpectedly, 23.3 % of HCC express chimeras between HBx protein and host LINE1 sequences. These chimeric transcripts, named HBx-LINE1, have oncogenic effects as they activate Wnt signaling. It is currently unknown whether many viruses can benefit from transcription of chimeric lncRNAs.

3. 2. Function of lncRNAs in infected cells

Given that viruses have such compact genomes and packaging of nucleic acids into virions is at a premium it is reasonable to surmise that every viral lncRNA should have a relevant function. Similar to what has been described for cellular lncRNAs, functionality requires RNA structure and lncRNA binding to other factors such as proteins or other transcripts. The structure of several lncRNAs has been studied in detail. Some viroid RNAs have self-complementarity to form rod-shape structures (Gago-Zachert, 2015). Their dsRNA nature protects the viroid genome but makes it targetable by the cellular RNA interference (RNAi) machinery. Structure of EBERs and VA RNAs is very similar and in fact EBERs can partially substitute VA RNAs in adenoviral infections (Rosa et al., 1981). In some cases the secondary structure is required for protein binding. Many cellular proteins have been described to bind viral ncRNAs. These include:

  1. Proteins required for RNA processing, such as Xrn1 in the case of sfRNAs (see above) or La in the case of EBERs and VA RNAs. La is required for proper folding and stability of polymerase III transcripts (Copela et al., 2006).

  2. Factors from the RNAi machinery: Exportin 5 and Dicer.

  3. Proteins involved in the immune response: Canonical and non-canonical sensors and mediators of IFN synthesis and signaling.

  4. Transcription regulators: transcription factors and chromatin modifying factors.

Binding to ncRNAs alters protein functionality. In some cases the protein is sequestered or mislocalized by interactions with the ncRNA (Imamura et al., 2014). There are also examples of protein destabilization upon binding to ncRNAs (Manokaran et al., 2015). Similarly, some lncRNAs bind cellular RNAs, including miRNAs (Lee et al. 2015; Cazalla et al., 2010). This serves, for example, to localize specific factors close to a target or to alter the stability or function of the miRNAs. All these interactions translate into functional effects in the infected cell.

3.2.1. Viral replication

Viroid genomes are circular, single-stranded RNA molecules capable of autonomous replication (Gago-Zachert, 2015). Replication occurs by a rolling-circle mechanism that involves three steps: generation of polymers containing multiple copies of the genome, cleavage of the polymers to monomers and circularization of the monomers. Nuclear viroids replicate using as host factors the RNA polymerase II and the ligase I. Interestingly, they have managed to redirect the DNA dependent RNA polymerase II and the DNA ligase I to function on viroid RNA sequences. In the case of chloroplastic viroids cleavage is carried out by a hammerhead ribozyme motif contained within the viral genome (Navarro and Flores., 1997).

3.2.2. Regulation of gene expression

Several lncRNAs expressed in the infected cells are used to regulate the expression of viral and host genes.

3.2.2.1. Regulation of gene expression by affecting transcription

In most cases described to date, regulation of viral gene expression by lncRNAs is exerted at the level of transcription and this may change early-to-late infection or latent-to-lytic phase. Several examples exist. Human citomegalovirus (CMV) RNA 4.9 binds the repressive complex PRC2 to inhibit immediate-early transcription during latency (Rossetto et al., 2013a; Noriega et al., 2014). Similarly, PAN RNA interacts with LANA, the KSHV latency associated nuclear antigen. LANA is expressed during latency to repress expression from the promoters of lytic genes. When PAN RNA is expressed, PAN binds to LANA and blocks LANAs DNA binding activity, leading to activation of the lytic cycle (Conrad et al., 2015; Campbell et al., 2014). Further, PAN RNA can also regulate gene expression by binding viral and cellular promoters and factors required for chromatin remodeling (Rossetto et al., 2013b). It has been shown than PAN RNA can bind the promoter of the viral lytic regulator Rta and the demethylases JMJD3 (Jumonji domain containing 3) and UTX (ubiquitously transcribed tetratricopeptide repeat, X chromosome) (Rossetto et al., 2013b; Rossetto and Pari, 2012). In PAN knocked-out mutants, JMJD3 and UTX association with the Rta promoter decreases and the repressive H3K27 trimethylation at the Rta promoter is higher (Rossetto and Pari, 2012). Interestingly, PAN RNA can also bind the activating methyltransferase MLL2 (mixed-lineage leukemia protein 2), indicating that PAN could bind promoters of viral genes to eliminate repressive marks and add activating chromatin marks (Rossetto and Pari, 2012). As PAN RNA can also bind to proteins of the repressive PRC2 (polycomb repressive complex 2) such as SUZ12 (suppressor of zeste 12) and EZH2 (enhancer of zeste 2), it has been suggested that it can also work as a negative regulator (Rossetto et al., 2013b). Finally, PAN RNA can also bind the transcription factor IRF4 and block transcription of cellular targets (Rossetto and Pari, 2011). PAN RNA expression results in decreased expression of several immune responsive genes and in increased cell proliferation (Rossetto et al., 2013b).

Other viral lncRNAs have also been shown to bind chromatin or transcription factors. Antisense HIV transcripts repress HIV expression (Kobayashi-Ishihara et al., 2012; Saayman et al., 2014) by binding silencing factors such as DNA methyltransferase 3A (DNMT3a), EZH2 and HDAC1 (histone deacetylase 1) (Lazar et al., 2015). EBER2 can also localize to specific sites of DNA to guide a transcription factor (Lee et al. 2015; Tycowski et al., 2015). EBER2 binding occurs at the terminal repeats of the latent EBV genome, where the master regulator of B-lymphocytes PAX5 (paired box protein 5) also binds. Thus, EBER2 and PAX5 function to decrease the expression of genes located close to the terminal repeats and increase lytic replication. In fact, PAX5 is recruited by EBER2 to the EBV DNA. Interestingly, EBER2 binding to DNA requires that EBER2 base-pairs with nascent transcripts derived from the terminal repeats. It would be interesting to identify whether cellular lncRNAs can guide transcription factors to specific position in the genome by base-pairing to nascent transcripts.

HIV viruses use several mechanisms to control expression of host and viral genes, including by affecting functionality of cellular transcription factors. As described above, HIV viral proteins regulate the expression of NRON, which, in turn, regulates NFAT activity. NRON is a cytoplasmic lncRNA that forms a ribonucleoprotein complex together with NFAT kinases and NFAT (Willingham et al., 2005; Sharma et al., 2011). The complex keeps NFAT phosphorylated and retained in the cytoplasm. Upon NRON depletion, NFAT can be dephosphorylated by calcineurin and translocated to the nucleus to activate expression of several host and HIV virus genes (Lazar et al., 2015; Aune and Spurlock, 2015).

3.2.2.2. Regulation of gene expression by affecting RNA stability

Regulation of host gene expression is exerted mainly by transcription regulation (see above) but also by affecting RNA stability. This is achieved by the control of exoribonucleases such as Xrn1 or by using the RNAi pathway. As explained above, sfRNAs are produced by stalled Xrn1 (Charley and Wilusz, 2015). As a result, the Xrn1 enzyme is repressed and flavivirus infected cells accumulate Xrn1 substrates such as decapped mRNAs (Moon et al., 2012; Moon et al., 2015; Jinek et al., 2011). Surprisingly, in cells infected by some flaviviruses, it seems that the entire 5′ to 3′ decay pathway is repressed, leading to the accumulation and translation of otherwise unstable transcripts and a dramatic dysregulation of cellular gene expression (Moon et al., 2012; Moon et al., 2015). As expected, deregulated genes include normally short-lived cytokines, growth factors, cell cycle regulators and oncogenes (Rigby and Rehwinkel, 2015). Therefore, Xrn1 inactivation could be the underline mechanism that results in the cytokine storm observed during some flavivirus infections and in the oncogenic potential of HCV-infected cells (Pijlman et al., 2008; Carnero and Fortes, 2015).

Besides Xrn1 inhibition, sfRNAs can repress the RNAi machinery in both insect and mammalian cells (Schnettler et al., 2012; Schnettler et al., 2014). This could be achieved by sequestration of Dicer due to the large amount of secondary structure in the sfRNA. This is similar to what has been described for VA RNAs. The structure and the high abundancy of VA RNAs allow the saturation of several key members of the RNAi pathway such as Exportin 5 and Dicer (Andersson et al., 2005). Interestingly, at the same time, VA RNAs are processed by the RNAi machinery to produce viral micro RNAs that are not essential for lytic replication (Andersson et al., 2005; Aparicio et al., 2006; Aparicio et al., 2010; Kamel et al., 2013). However, these VA RNA-derived miRNAs can alter the expression of host cell genes. Finally, cells infected with viroids contain dsRNAs present in the highly structured regions of the genome or generated by genome replication. These dsRNA viroid molecules are processed by the cellular RNAi machinery to produce antiviral small interference RNAs (siRNAs) (Molnar et al., 2005; Mlotshwa et al., 2008; Gago-Zachert, 2015). Some viroid-derived siRNAs can also target cellular genes and result in several of the symptoms associated with viroid infection (Eamens et al., 2014).

The interplay between the RNAi machinery and the viral lncRNAs is also observed in cells infected with Herpesvirus saimiri (HVS). Latent infection with HVS produces high amounts of several HSURs (HVS U-rich RNAs) (Lee at al., 1988). HSUR1 and 2 are required for efficient viral replication and their expression results in upregulation of several host genes involved in T-cell activation (Murthy et al., 1989; Cook et al., 2005). This is mediated by HSUR1 binding and degradation of miR27 (Cazalla et al., 2010). After degradation of miR27, miR27 targets are increased and lead to T-cell activation and, probably, to proliferation of HVS-infected T cells (Tycowski et al., 2015). Several cellular lncRNAs have been described to interact with miRNAs. In most cases, they behave as sponges that sequester miRNAs and lead to the upregulation of miR-target genes. This is the case of HULC (highly upregulated in liver cancer), a lncRNA whose expression is particularly increased in the liver and serum of patients with HCC and an underlying HBV infection and serves as a marker for poor prognosis (Xie et al., 2013; Panzitt et al., 2007). A single nucleotide polymorphism in HULC shows decreased susceptibility to developing HCC in chronic HBV patients (Liu et al., 2012). HBx from HBV seems in charge of HULC upregulation and HULC silencing blocks HBx protein-mediated enhanced cell proliferation (Du et al., 2012; Wang et al., 2010). Interestingly, HULC sequesters miR-372, involved in regulation of cell cycle, apoptosis, invasion, and proliferation in many types of human cancers (Wu et al., 2015).

3.2.3. Regulation of the antiviral response

Within the regulation of host genes, control of those required to build an antiviral response deserves a special chapter. It is expected that viral lncRNAs should decrease the antiviral response, while cellular lncRNAs induced by infection could either induce the pathway or decrease IFN synthesis and signaling to control the duration and the strength of the antiviral response.

3.2.3.1. Control of the antiviral response by viral ncRNAs

Viral ncRNAs can be detected by several canonical and non-canonical PAMP sensors, such as TLR3, RIG-I, PKR and OAS, and induce the antiviral pathway. RIG-I is activated by dsRNAs with a triphosphate group at their 5′ end. This is a characteristic of EBERs and VA RNAs. Therefore, both EBERs and VA RNAs should activate RIG-I and led to IFN production (Iwakiri, 2015; Vachon and Conn, 2015). Further, VA RNAs can also activate OAS, which is another sensor for dsRNA. OAS synthesizes 2′-5′-linked oligoadenylate second messengers that activate RNase L, an endoribonuclease able to degrade single stranded RNAs. These RNA fragments can enhance RIG-I activation, leading to a further amplification of the IFN response (Malathi et al., 2007). Finally, EBERs are secreted by infected cells in complex with La protein (Iwakiri et al., 2009; Ahmed et al., 2014). Secreted EBERs activate TLR3 signaling in immune cells leading to production of inflammatory cytokines which could account for the immunopathologic diseases caused by EBV infection (Iwakiri et al., 2009; Iwakiri, 2015).

Interestingly, some ncRNAs have been described to block the activity of PKR or regulators, such as the RIG-I E3 ligase TRIM25. Both VA RNAs and EBERs are sensed by PKR, which requires a short dsRNA sequence. Interestingly, binding to PKR by these ncRNAs does not allow PKR activation. Instead, it avoids PKR dimerization and auto-phosphorylation. Therefore, signaling through PKR to eIF2a does not occur and translation of viral genes is properly initiated (Iwakiri, 2015; Vachon and Conn, 2015) (Fig. 1). In this case, therefore, the ncRNA behaves as a negative regulator of the antiviral pathway. Another negative regulator of the IFN synthesis pathway is sfRNA. Surprisingly, a particular sfRNA, PR-2B, has been described to bind TRIM25, an E3 ligase with unknown RNA binding capacity (Fig. 1). Binding of TRIM25 by PR-2B sfRNA prevents its deubiquitinylation by ubiquitin-specific peptidase 15 (USP15). Ubiquitinated TRIM25 is not active to polyubiquitinate and stabilize RIG-I, resulting in a dramatic decrease in the interferon response to infection by the cell (Manokaran et al., 2015).

3.2.3.2. Control of the antiviral response by cellular lncRNAs induced by infection
Positive regulators of the INF pathway

Among the lncRNAs induced by infection that function to activate the antiviral response are NEAT1 and BISPR (BST2 (Bone Marrow Stromal Antigen 2) IFN-stimulated positive regulator) (Fig. 1). IFN induces the expression of lncRNA BST2 or BISPR in several cell lines (Kambara et al., 2015; Barriocanal et al., 2015). BISPR is located head-to-head with BST2/tetherin, a well-characterized antiviral factor that attaches viruses to the cell surface and impedes viral release (Dafa-Berger et al., 2012; Neil et al., 2008). Both BISPR and BST2 are corregulated and it has been shown that BISPR acts in trans to induce transcription of BST2 gene, probably, by counteracting the repressive action of PRC2 (Kambara et al., 2015; Barriocanal et al., 2015).

HIV, influenza virus and other infections increase the levels of NEAT1, required for formation of paraspeckles (Zhang et al., 2013b; Clemson et al., 2009). Paraspeckles retain hyperedited and non-spliced RNAs such as many HIV RNAs. Further, paraspeckles retain the regulator SFPQ (Imamura et al., 2014). SFPQ is required for proper expression of several innate immune related genes, including IL8, RIG-I and MDA5. Increase of NEAT1 by HIV and other viruses, increases paraspeckles, decreases available SFPQ and augments IL8 and other antiviral factors (Landeras-Bueno and Ortín, 2015; Lazar et al., 2015) (Fig. 1).

Negative regulators of the IFN pathway

As mentioned above, many lncRNAs have been described to function as negative regulators of IFN synthesis or signaling and they could be required to help the cell to return to homeostasis after infection. Interestingly, some of these lncRNAs could be induced by certain viruses to counteract the cellular antiviral response. Many lncRNAs that negatively control the IFN pathway are regulated by activation of TLR receptors, such as lincRNA-COX2, IL7R or THRIL (Carpenter, 2015; Aune and Spurlock, 2015). Linc-RNA-COX2, induced after TLR activation, represses the expression of ISGs by binding hnRNP A/B proteins (heterogeneous nuclear ribonucleoprotein A/B) and, in part, by regulating the recruitment of RNA polymerase II to the promoter of target genes (Carpenter et al., 2013). Lnc-IL7R gene, induced after LPS and TLR2 stimulation, overlaps with the 3′UTR of the IL7R gene and functions as a negative regulator of the LPS-induced inflammatory response by regulating levels of H3K27 trimethylation at the promoters of target genes (Cui et al., 2014). THRIL (TNF-α and heterogeneous nuclear ribonucleoprotein L (hnRNP L) related immunoregulatory LincRNA), repressed by TLR and TNF activation, is required for induction of gene expression by binding hnRNP L and the promoter/enhancers of TNF targets (Li et al., 2014). While THRIL is indeed an inducer of TNF transcription, the fact that is downregulated by TLR and TNF activation results in decreased expression of target genes during the antiviral response. TNF also increases the expression of Lethe, a pseudogene of the ribosomal protein S15a (Rps15a) gene. Lethe inhibits NF-κB by titrating the RelA or p65 component of the active NF-κB p60/p65 heterodimer away from the NF-κB DNA response elements (Rapicavoli et al., 2013) (Fig. 1).

Similarly, IFN treatment induces the expression of NRIR gene (negative regulator of IFNα response), which is located in the genome close to two key ISGs: CMPK2 and viperin (Kambara et al., 2014). Surprisingly, NRIR expression inhibits transcription of CMPK2 and viperin, but also of other ISGs located far away in the genome, such as ISG15, CXCL10, IFIT3 or IFITM1 (Fig. 1). However, other ISGs such as Mx1, IFIT1 or IFNβ seemed resistant to NRIR. The molecular mechanism of transcription regulation is still unknown, but it could involve regulation of chromatin remodelling factors. This is the case of NRAV, a lncRNA downregulated by influenza virus expression (Ouyang et al., 2014). Downregulation of NRAV resulted in an increase in the H3K4me3 active mark and a decrease in the H3K27me3 repressive mark at the promoter of MxA and IFITM3 genes. Therefore, decreased levels of NRAV caused the upregulation of these ISGs.

3.2.4. Induction of mitochondrial energy

The most abundant lncRNA produced during the lytic infection with HCMV is expressed from the viral Beta 2.7 gene (Poole et al., 2015; Gatherer et al., 2011). Although with some coding potential, surprisingly, the RNA interacts with GRIM19 (genes associated with retinoid/IFN-induced mortality 19), a subunit of mitochondrial Complex I essential for complex assembly and function (Reeves et al., 2007). Binding of Beta 2.7 RNA to GRIM19 stabilizes mitochondrial membrane potential and results in continued ATP production, which is critical for the successful completion of the virus’ life cycle. Interestingly, interaction of the Beta 2.7 RNA with Complex I inhibits rotenone stress-induced apoptosis in neuronal cells.

3.2.5. Induction of pathogenesis

Some viral lncRNAs induce part of the pathogenicity exerted by viruses. It has been already described how viroid-derived siRNAs can target host genes and result in several plant symptoms, how inhibition of Xrn1 by sfRNA stabilizes short-lived cytokine mRNAs and may generate a cytokine storm associated to the infection or how secreted EBERs are sensed by TLR3 and lead to immunopathological diseases.

Similarly, it has been already described how HBV infection regulates the expression of several lncRNAs (DREH, HBx-LINE or HULC) which may mediate the increased risk of HCC development observed in HBV infected patients. Actually, chronic infection with either HBV or HCV leads to a chronic damage and liver inflammation that helps the development of HCC. In line with this, infection with HCV has been also shown to induce the expression of several lncRNAs with oncogenic potential (Carnero et al., submitted; Carnero and Fortes, 2015). Only in few cases the molecular mechanisms of oncogenicity have been studied in detail. DREH, inhibited by HBV infection, decreases proliferation by binding to vimentin (Huang et al., 2013); HBx-LINE induces the Wnt pathway by increasing the nuclear localization of b-catenin (Lau et al., 2014); HULC binds miR372 and avoids activation of CREB, cell proliferation and differentiation (Wang et al., 2010); HEIH (High Expression In HCC), increased in HBV-derived HCC, inhibits several cyclin dependent kinases by binding the repressive factor EZH2 (Yang et al., 2011); LET (Low Expression in Tumor), decreased in HBV-derived HCC, binds to and destabilizes NF90, a well-known regulator of factors related to tumor growth and metastasis (Yang et al., 2013b); MVIH (microvascular invasion in HCC), increased in HBV-derived HCCs, avoids secretion of PGK-1, which is an inhibitor of angiogenesis (Yuan et al., 2012); PVT-1 (plasmocytoma variant translocation 1), induced by HCV infection, is a positive regulator of c-myc (Tseng et al., 2014) and UCA1 (urothelial carcinoma associated 1), also increased by HCV infection, sequesters PTB and decreased PTB-mediated translation of p27, causing a decrease of this tumor suppressor (Huang et al., 2014).

Final considerations

Investigation into the role and function of lncRNAs in viral infections is still largely in its infancy. Future studies are required to understand in depth how the lncRNA transcriptome is altered in the infected cell and how these alterations impact viral fitness and cell survival. These studies may help to identify novel cellular pathways. In fact, studies with viruses have been transformative with regards to our collective knowledge of several key steps of gene expression such as transcription, splicing, polyadenylation and transport. More recently, the study of the stability of PAN RNA has allowed the discovery of a novel nuclear decay pathway and the identification of a triple helix structure that serves to stabilize viral and cellular transcripts (Wilusz et al., 2012; Brown et al., 2012; Brown et al., 2014). In line with this, it would be very interesting to determine whether Xrn1 serves to process cellular RNAs similarly to how it processes sfRNAs.

Furthermore, it is expected that the study of lncRNAs in infected cells leads to the development of RNAs with therapeutic relevance. In fact, this has been already proven to be the case for Beta 2.7 RNA, involved in the induction of mitochondrial energy (Poole et al., 2015). A domain of Beta 2.7 RNA has been identified that retains the functionality of the full-length transcript (Kuan et al., 2012). When bound to a RVG peptide with 9 arginine residues (RVG-9R), which crosses the blood-brain barrier, it can be delivered to neurons (Kuan et al., 2012; Kumar et al., 2007). There, the Beta 2.7 domain can protect mitochondrial complex I from stress-induced apoptosis and avoid neuron death. This treatment protects dopaminergic neurons in a rat model of Parkinson disease and could also be applied for the treatment of other mitochondrial and neurological diseases.

Finally, some viral lncRNAs may be used as therapeutic targets. This may be especially relevant for those lncRNAs that are expressed in latent infections, with the aim of eliminating latency-infected populations (Lazar et al., 2015). Similarly, virus-related lncRNAs secreted into the serum may serve as prognostic markers for disease progression. Interestingly, the fact that several lncRNAs behave as inducers or inhibitors of the IFN response, suggests that by modulating the cellular levels of these lncRNAs, the IFN response can be enhanced or repressed. This modulation may have therapeutic relevance for the treatment of several autoimmune diseases, viral infections and cancer.

Highlights.

  1. Infected cells change their transcriptome to express proviral and antiviral lncRNAs.

  2. Many viruses express viral noncoding transcripts essential for viral viability.

  3. Many lncRNAs expressed in the infected cell function as positive or negative regulators of the innate antiviral response.

Acknowledgments

We want to apologize to all the scientists whose work has not been mentioned due to space limitations. This study was supported by grants from the Ministry of Science and Innovation (BIO2009/09295, SAF2012-40003, BFU2013-50517-EXP), Fondo de Investigación Sanitaria (PI13/01989), financed by the Instituto de Salud Carlos III, Fundació La Marató de TV3 (20132130-31-32), Caja Navarra Foundation (70020), FEDER funding, funds from the “UTE project CIMA” and by the project RNAREG [CSD2009-00080], funded by the Ministry of Science and Innovation under the program CONSOLIDER INGENIO 2010. Support for KVM is acknowledged from NIAID PO1 AI099783-01, R01 AI111139-01, R01 DK104681-01 and Australian Research Council FT1300100572.

Footnotes

The authors declare no conflict of interest.

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