Zhang et al. Retrovirology (2018) 15:20 https://doi.org/10.1186/s12977-018-0403-8 Retrovirology REVIEW Open Access Non‑coding RNAs and retroviruses Xu Zhang1,2,3, Xiancai Ma1,2,3, Shuliang Jing1,2,3, Hui Zhang1,2,3* and Yijun Zhang4* Abstract Retroviruses can cause severe diseases such as cancer and acquired immunodefciency syndrome. A unique feature in the life cycle of retroviruses is that their RNA genome is reverse transcribed into double-stranded DNA, which then integrates into the host genome to exploit the host machinery for their benefts. The metazoan genome encodes numerous non-coding RNAs (ncRNA), which act as key regulators in essential cellular processes such as antiviral response. The development of next-generation sequencing technology has greatly accelerated the detection of ncRNAs from viruses and their hosts. ncRNAs have been shown to play important roles in the retroviral life cycle and virus–host interactions. Here, we review recent advances in ncRNA studies with special focus on those have changed our understanding of retroviruses or provided novel strategies to treat retrovirus-related diseases. Many ncRNAs such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are involved in the late phase of the retroviral life cycle. However, their roles in the early phase of viral replication merit further investigations. Keywords: Non-coding RNA, Retroviruses, Viral life cycle, Virus latency, MicroRNA, Long non-coding RNA Background people living with HIV-1 worldwide, with approximately The classifcation and life cycle of retroviruses 2.1 million new infections being reported in 2015. To Retroviruses represent a large and diverse family of date, there is no cure for AIDS because of the existence enveloped RNA viruses defned by common taxonomic of the HIV reservoir. Te latent reservoir is a group of denominators that include structure, composition, and HIV-infected cells (mainly resting ­CD4+ T cells) that do replicative properties [1]. A key feature of the retroviral not actively produce new HIV-1, but could produce virus life cycle is that the RNA genome is reverse-transcribed again upon stimulation [3]. to double-stranded DNA, which is subsequently inte- Te life cycle of retroviruses can be simply divided into grated into the host genome and turns to a provirus. Te the early and late phases. Te early phase refers to the viral genes are transcribed from the integrated proviral steps from cell binding to integration of the viral cDNA in DNA to produce proteins and genomic RNA required the host genome, whereas the late phase begins with the to assemble the progeny viral particles. Retroviruses are expression of viral genes and is followed by the assembly, further subdivided into seven groups (genus) defned by release, and maturation of progeny virions [4]. For HIV- their evolutionary relatedness [2]. Retroviruses in fve of 1, the lifecycle can be briefy divided into seven steps: (1) these groups have oncogenic potential (formerly referred attachment and binding, (2) fusion and uncoating, (3) to as oncoviruses), and the other two groups are lentivi- reverse transcription, (4) integration, (5) transcription, ruses and spumaviruses. Te representative of the lenti- (6) assembly, and (7) budding (Fig. 1A–G). Steps 1–4 rep- virus family is the human immunodefciency virus type resent the early phase, and steps 5–7 represent the late 1 (HIV-1), the causative agent of acquired immunode- phase of a typical retrovirus life cycle. In addition, there fciency syndrome (AIDS). Tere are over 36 million is a special state of the retrovirus life cycle called latent infection. Under such conditions, the proviral DNA is *Correspondence: [email protected]; yi‑[email protected] transcriptionally inactive without producing infectious 1 Institute of Human Virology, Zhongshan School of Medicine, Sun Yat- viral particles. As the host CD4­ + T cells are activated, the Sen University, Guangzhou 510080, China phase of latent HIV infection can be reversed to produc- 4 Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA tive infection [3, 5]. Numerous host factors are involved Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Zhang et al. Retrovirology (2018) 15:20 Page 2 of 14 Fig. 1 Non-coding RNAs and HIV-1 life cycle. The life cycle of HIV-1 includes: attachment and binding, fusion and uncoating, reverse transcription, integration, transcription, assembly, budding and latency. The roles of representative microRNAs and long non-coding RNAs in HIV-1 life cycle are shown. RT reverse transcriptase; A3G APOBEC3G; AGO Argonaute protein; LEDGF lens epithelium-derived growth factor or p75; HDFs host depend- ency factors; miRNA microRNA; siRNA small interfering RNA in the life cycle of retroviruses, being either indispensable signal (NES), which was the frst NES described, and or restrictive [6]. still remains the prototype of the most common class of Virology and RNA biology have reciprocally infuenced NESs [12]. Compatible with such signifcant progress in each other for decades [7]. Te capping of eukaryotic virus research, the recent advances in non-coding RNA mRNA was frst discovered in reovirus and vaccinia virus (ncRNA) research have greatly extended our understand- [8]. Splicing and then alternative splicing were frst dem- ing of viruses. onstrated by analysis of adenoviral transcription [9, 10]. Analysis of viral systems, in particular picornaviruses, The classifcation and functions of non‑coding RNAs led to the frst description of an internal ribosome entry Genomic studies have demonstrated that only two per- site (IRES) [7]. Retroviruses have also played an impor- cent of the human genome codes for proteins, whereas tant role in understanding the export of mRNAs from the the majority codes for numerous non-protein coding nucleus to the cytoplasm. For host transcripts, only fully RNAs (or non-coding RNA, ncRNA) [13]. Based on spliced mRNAs can be exported to the cytoplasm. How- their function, non-coding RNAs can be divided into ever, for some retroviruses such as HIV-1, both spliced two major groups: (1) housekeeping non-coding RNA and unspliced transcripts need to be exported to the such as ribosomal RNA (rRNA), transfer RNA (tRNA), cytoplasm to produce viral proteins or serve as genomic small nuclear RNA (snRNA), and small nucleolar RNA RNA. HIV-1 encodes a special protein called Rev that (snoRNA); and (2) regulatory non-coding RNA such as exports its unspliced mRNA transcripts containing the microRNA (miRNA), long non-coding RNA (lncRNA), Rev Response Element (RRE) to the cytoplasm [11]. To and piwi-interacting RNA (piRNA) [14]. Te house- accomplish this function, Rev harbors a nuclear export keeping non-coding RNAs are mainly involved in the Zhang et al. Retrovirology (2018) 15:20 Page 3 of 14 basic biological processes in cells, such as snRNA for the 3′ UTR of mRNAs to suppress translation or induce pre-mRNA splicing, rRNA and tRNA for mRNA transla- degradation. Unlike siRNAs, which fully complement tion, snoRNA for rRNA methylation/pseudouridylation. to their target mRNA, most miRNAs bind to the target However, the regulatory non-coding RNAs exert more mRNA mainly through the “seed sequence”, residues 2–8 diverse and sophisticated functions such as miRNA for of the guide miRNAs (Fig. 1H). Te regulatory target regulating gene transcription and translation, lncRNA sequences of miRNA have been extended to the 5′ UTR for modifying epigenetic signatures of chromatin, and [28] and the coding region [29] of mRNAs to suppress piRNA for silencing transposons [14]. Unlike housekeep- translation. Moreover, miRNAs could switch from sup- ing ncRNAs, the expression of regulatory ncRNAs is usu- pressor to activator of translation by targeting the 5′ UTR ally tissue-specifc and their regulation is gene-specifc, [30] or 3′ UTR [31] of certain mRNAs. In addition to which is mostly enabled by sequence-specifc interac- regulating mRNA translation in the cytoplasm, mounting tions between the ncRNA and its target(s) [15]. During evidence reveals that the small RNA-Ago pathway can viral infection, the regulatory ncRNAs exhibit more pro- also positively regulate gene expression by targeting gene found changes in expression and sophisticated functions promoters in the nucleus, a phenomenon termed as RNA compared to the housekeeping ncRNAs [16]. activation (RNAa), which is evolutionarily conserved from Caenorhabditis elegans to human [32–35]. RNA interference and microRNA RNA interference (RNAi) was proposed to initially evolve Long non‑coding RNAs in plants and invertebrates as a native immune response Te ENCODE (Te Encyclopedia of DNA Elements) against viruses [17]. In plant and invertebrate cells, the Project led to the discovery of a large proportion of long infection of all RNA viruses, except retroviruses, leads transcripts from the human genome that do not code to the generation of perfectly base-paired long double proteins (long non-coding RNAs, lncRNAs) [36]. lncR- stranded RNAs (dsRNA), which are cleaved by the exo- NAs can be operationally defned as RNA transcripts nuclease Dicer into ~ 22 bp short dsRNAs named small larger than 200 bp without any coding potential [37]. interfering RNA (siRNA) [17]. Tis is also true for some Tey appear in the genome in three major forms: anti- DNA viruses. One strand of the siRNA duplex is loaded sense lncRNAs, intronic lncRNAs, and intergenic lncR- into the RNA-induced silencing complex (RISC), where NAs (also termed large intervening noncoding RNAs or it guides RISC to mRNA containing complementary lincRNAs).