Putting an ‘End’ to HIV mRNAs: capping and polyadenylation as potential therapeutic targets
© Wilusz; licensee BioMed Central Ltd. 2013
Received: 17 October 2013
Accepted: 26 November 2013
Published: 13 December 2013
Like most cellular mRNAs, the 5′ end of HIV mRNAs is capped and the 3′ end matured by the process of polyadenylation. There are, however, several rather unique and interesting aspects of these post-transcriptional processes on HIV transcripts. Capping of the highly structured 5′ end of HIV mRNAs is influenced by the viral TAT protein and a population of HIV mRNAs contains a trimethyl-G cap reminiscent of U snRNAs involved in splicing. HIV polyadenylation involves active repression of a promoter-proximal polyadenylation signal, auxiliary upstream regulatory elements and moonlighting polyadenylation factors that have additional impacts on HIV biology outside of the constraints of classical mRNA 3’ end formation. This review describes these post-transcriptional novelties of HIV gene expression as well as their implications in viral biology and as possible targets for therapeutic intervention.
Our appreciation of the overall impact and importance of post-transcriptional processes on eukaryotic – and Human Immunodeficiency Virus (HIV) – gene expression has significantly expanded over the last decade. The nuclear processes of pre-mRNA capping, splicing and polyadenylation are now considered largely co-transcriptional in nature and each exerts considerable influence on the transcription process itself [1, 2]. Alternative splicing, and to some surprise polyadenylation as well, play a major role in shaping the transcriptome [3, 4]. The regulation of the efficiency of nuclear export of HIV transcripts through the Rev/RRE system is well-characterized . Interestingly, recent data suggest a significant amount of ‘two-way’ communication between the stability of an RNA in the cytoplasm and its transcription rate [6, 7]. The processes of translation, RNA editing and miRNA-mediated regulation also influence the outcome of HIV gene expression [8–10]. Thus a clear understanding of HIV post-transcriptional events is important for a full appreciation of HIV biology and HIV-host interactions. In addition to their value in understanding basic HIV biology, these new insights into post-transcriptional regulation of HIV gene expression have opened up several novel avenues for possible antiviral therapeutic targeting. Since several aspects of HIV post-transcription control (e.g. splicing, Rev/RRE mediated export, RNA editing) have been the subject of recent reviews [5, 9, 11], this review will focus on the regulation and impact of HIV mRNA terminal modifications – namely 5′ capping and 3′ polyadenylation - have on HIV gene expression and their potential value as therapeutic targets. Recent insights in these two areas, combined with their fundamental importance to HIV molecular biology, make them rather interesting and attractive processes from both a basic and translational scientific perspective.
HIV RNA capping – a novel way to put a ‘lid’ on HIV gene expression?
All eukaryotic mRNAs contain a 5′ 7meGpppG ‘cap’ on their 5′ end that is added co-transcriptionally after the first ~20-40 nucleotides of the mRNA are synthesized by RNA polymerase II . Cap addition requires three enzymatic activities – an RNA triphosphatase, a guanyltransferase, and an m7guanine methyltransferase – that are present in two proteins that make up the enzymatic components of the human capping enzyme  that HIV usurps to cap its own mRNAs. These enzymes are brought to the nascent pre-mRNA by association with the Carboxyl-Terminal Domain (CTD) of the large subunit of RNA Pol II in a phosphorylation-mediated fashion . Interestingly, it has been recently demonstrated that mammalian cells contain a surveillance machinery anchored by the DXO and Xrn2 factors that will rapidly degrade incorrectly capped pre-mRNAs [15, 16]. Capping also influences the nuclear processes of transcription , splicing  and 3′ end formation/polyadenylation . Through interaction with the two proteins of the cap binding complex (CBC), the cap placed on mRNAs driven from the HIV1 promoter up-regulates transcriptional elongation and influences alternative splicing patterns . If one depletes the CBC, TAT- transactivation and transcription elongation are repressed from the HIV1 promoter . In the cytoplasm, the cap is essential for efficient mRNA translation  and is a key target for the turnover of mRNAs . Thus it is vitally important for HIV to efficiently cap its mRNAs to maintain a high level of gene expression.
Interfering with the fundamental process of capping of several RNA viruses has been tapped as a potential antiviral target due to the use of viral-derived capping enzymes that bear distinct structures and enzymatic mechanisms [24, 25]. This approach is not feasible as an HIV target since the virus utilizes host enzymes to mature the 5′ end of its mRNA. Thus one needs to focus on apparent HIV nuances of the capping process, three of which we believe may pose interesting possibilities as drug targets.
The HIV Tat protein, a small basic intrinsically disordered protein, is well known to interact with the TAR element on the HIV mRNA and recruits transcription factors to promote HIV gene expression . However it is clear that the Tat protein is multi-functional in nature and may also influence RNA interference , splicing , and notably mRNA capping. The Tat protein stimulates the capping of nascent HIV transcripts by either a direct interaction with the Mce1 component of the human capping enzyme [29, 30] or through stimulating the phosphorylation of the CTD of the large subunit of RNA Pol II . Tat also has nucleic acid chaperone activity which may contribute to its ability to stimulate RNA capping . While inhibitors that target Tat interactions as potential anti-HIV therapeutics have been studied for some time e.g. [33–36], perhaps targeting the C-terminal region of Tat that interacts with the Mce1 capping enzyme  might be a fruitful approach as well. One potential limitation to this approach, however, is that a firm grasp on the structure of the flexible Tat protein has been elusive.
A second potential therapeutic avenue to follow in HIV capping is the observation that some HIV mRNAs contain 2,2,7 trimethylated guanosine caps instead of the standard 7meG cap found on mRNAs . Interestingly, there are several reports that other RNA viruses (a flavivirus and two alphaviruses) also can contain di- and tri-methylated caps on their RNAs [38–40]. Trimethylation of HIV mRNA caps appears to enhance RNA export and improve HIV gene expression . Cap hypermethylation is likely mediated by the cellular PIMT enzyme, a ubiquitously expressed protein that can be found in both the nucleus and cytoplasm of mammalian cells and is best studied for hypermethylation of U small RNA caps involved in splicing . PIMT appears to be recruited to HIV mRNAs via REV/RRE interactions. Overexpression of PIMT can enhance HIV gene expression, while knocking down the enzyme has the converse effect . Interestingly, PIMT activity may be limiting in quiescent cells, and thus be a contributing factor to HIV latency. It is also possible that HIV cap hypermethylation may disrupt U snRNA biogenesis and/or nuclear export. This could impact cellular mRNA splicing, reducing the ability of the HIV infected cells to effectively react to the virus. Thus PIMT and HIV cap hypermethylation may represent an interesting target for therapeutic intervention. Several methylation inhibiting drugs (e.g. the S-adenosyl methionine (SAM) analogue sinefungin, 3-deaza-adenosine and neplanocin A and F analogs) have been shown to decrease HIV replication [37, 42–45]. However given the fact that there are numerous enzymes that use SAM and/or methylate cellular substrates, including over 50 lysine methylases, a challenge will be to identify or rationally design small molecule inhibitors that are specific for PIMT. As an alternative strategy, determining ways to increase PIMT activities in quiescent cells may be a viable approach to help drive HIV out of latency and deplete troublesome viral reservoirs. Additional studies to more firmly establish the relationship of PIMT to HIV quiescence would of course be needed to ascertain the likelihood of success with such a strategy. Finally, although highly speculative, this uncommon hypermethylation of HIV caps could be exploited for the specific targeting therapeutics. Since antibodies are capable of specifically recognizing tri-methylated caps, it may be possible to engineer small aptamers that specifically target trimethylated caps in the context of the highly structured 5′ terminal portion of HIV mRNAs.
A final curiosity regarding the 5′ cap is that in both HIV1 and HIV2, the 5′ capped nucleotide is located at the base of a stem in an area of extensive and highly stable secondary structure . In fact, HIV mRNAs require the DDX3 helicase which appears to substitute for the eIF4E cap binding protein to promote translation [47, 48]. This structured region may also protect the cap from quality-control surveillance in the nucleus  and increase the stability of HIV RNAs by making it difficult for 5′-3′ exonucleases to gain access to an exposed 5′ end. If this is true, then decapped HIV mRNAs may be differentially stabilized in infected cells – and could even be substrates for the recently identified process of cytoplasmic ‘recapping’ of RNAs . Thus small molecules that target aspects of these structures may be useful in reducing HIV gene expression by exposing the cap to normal cellular regulatory controls.
HIV polyadenylation - can we figure out a way to get an ‘A’ in our course (of treatment)?
The process of 3′ end formation/polyadenylation occurs co-transcriptionally on cellular and HIV mRNAs generated by RNA Pol II and influences the termination of transcription at a site several hundred bases downstream of the mature 3′ end of the mRNA . The 3′ end of most human mRNAs is generated first by an endonucleolytic cleavage event (catalyzed by CPSF73, aka CPSF3) followed by the addition of 100–250 adenylate residues by poly(A) polymerase (PAP). A typical polyadenylation signal contains two types of elements. The core elements consist of an AAUAAA or similar hexanucleotide and a short (about 5 base long) U- or GU-rich tract located within approximately 25–30 bases upstream or downstream, respectively, of the site. The core elements serve as the assembly site of the complex of polyadenylation factors. Many polyadenylation signals also contain auxiliary elements that are located upstream or downstream of the core elements. These auxiliary elements bind to a variety of cellular factors and influence the efficiency of polyadenylation. There are at least 13 core polyadenylation factors and perhaps up to 80 proteins that interact with the complex that forms on the pre-mRNA substrate to generate the mature mRNA 3′ end . This high degree of complexity for the polyadenylation machinery is likely designed to (a) control/target the endonuclease and template independent poly(A) polymerase; (b) network polyadenylation with transcription, capping, splicing and export processes in the nucleus [1, 19, 52]; and (c) to regulate alternative polyadenylation .
Polyadenylation is far from the default process that is typically depicted in textbook descriptions of gene expression. Data generated over the last several years has firmly established the dynamic, highly regulated nature of polyadenylation site choice. Well over 50% of genes are subject to alternative polyadenylation and the process is highly regulated in a tissue-specific and developmentally-specific fashion [53–55]. Altering the site of polyadenylation can truncate protein open reading frames, change splicing patterns or alter mRNA posttranscriptional regulation by shortening the 3′ untranslated region (UTR) and removing sites for miRNA or RNA binding factor interactions . Interestingly, HIV has two polyadenylation signals in its mRNA as a result of the duplicated signal present in the LTR regions . The virus must suppress use of the upstream 5′ polyadenylation site or the short mRNA that is generated will not contain an open reading frame. Additionally, the efficiency of the recognition of the normal 3′ polyadenylation site also has potential pathogenic implications for HIV since the read-though of the normal polyadenylation site is associated with transductive recombination [57, 58]. Given the fundamental importance of polyadenylation to HIV gene expression as well the recognition that the process interfaces with numerous nuclear processes and regulatory checkpoints, we believe that at least two aspects of polyadenylation might present possible targets for therapeutic intervention.
A first possible target is the HIV-specific aspects of poly(A) site usage that may in some ways be selectively used by the virus and not the majority of cellular poly(A) signals. Auxiliary elements occur upstream of the normal HIV polyadenylation signal and greatly stimulate its usage. These elements are not located upstream of the 5′ promoter-proximal polyadenylation site due to where transcription begins in the HIV LTR. First suggested by LTR 3′ region deletion experiments performed in the Cullen , Ganem  and Alwine laboratories , the sequence and structural requirements of this 3′ auxiliary element have been extensively studied by Gilmartin and colleagues. Upstream auxiliary sequences that influence HIV polyadenylation appear to include 76 bases upstream of the AAUAAA. This region includes the TAR structural element  and importantly a sequence region upstream that collectively assist in the assembly of the core polyadenylation factors, including CPSF and CF1m [62–64] on the downstream polyadenylation region. Given the highly structured nature of this region [46, 65, 66], it may be possible to develop small molecule inhibitors to disconnect this upstream enhancer function from the HIV polyadenylation signal, resulting in a dramatic decrease in HIV gene expression. RNA structures are viable drug targets as, for example, numerous antibiotics target RNA-derived structures in the ribosome and branched boronic peptides have recently been shown to target the HIV RRE . Alternatively, work in the Proudfoot and Cochrane laboratories has suggested a clear association in the efficiency of HIV polyadenylation and the major 5′ splice site [68, 69]. Therefore drugs that influence splicing factors/RNA splicing may have some desirable consequences on HIV gene expression. To date, several studies have presented mixed results targeting a U1 snRNP-based polyadenylation/splicing related inhibition approach to HIV therapy [70, 71]. Thus more work is clearly needed in this area. Next, while promoter proximity of the HIV upstream 5′ polyadenylation site clearly represses its activity [60, 72], a recent study has demonstrated that activating a cryptic polyadenylation site near promoters can decrease transcriptional activity . Thus determining ways to de-repress the promoter-proximal HIV poly(A) site may yield huge therapeutic dividends. Finally Goff and colleagues have demonstrated using genetic screens and other analyses that HIV polyadenylation is directly regulated by eIF3f, CDK11, and splice factor 9G8 . Thus compounds that regulate a variety of cellular proteins may be capable of repressing HIV polyadenylation and produce some clinical benefit if effects on host cell metabolism can be minimized.
The second possible area of HIV polyadenylation-related therapeutic development may lie in a bevy of unexpected roles for polyadenylation factors that have recently been demonstrated in HIV biology. It is becoming clearer in the field of post-transcriptional control of gene expression that many processes are networked and factors can appear to be ‘moonlighting’ to perform a variety of functions in the cell. Along these lines, CPSF6 (aka CF1m68kd) has been shown to have isoforms that bind HIV capsid protein and regulate HIV disassembly and trafficking to the nucleus [75–77]. Thus small molecules that stabilize or promote the formation of cytoplasmic CPSF6 isoforms may have significant impact on multiple aspects of HIV biology. CPSF3 (aka CPSF73) has been demonstrated to be up-regulated by TAT and repress the HIV promoter [78, 79]. Hence targeting this factor could have some impact on driving HIV out of latency in reservoir sites. The polyadenylation and transcription termination factor Pcf11 has been shown to be a negative elongation factor for HIV . Thus, stabilizing or increasing the activity of this protein may have therapeutic benefits. Finally, hyperphosphorylation of poly(A) polymerase (PAP) has been shown to be associated with HIV Vpr expression . Thus this may need to be considered when analyzing the effect of various kinase inhibitors on HIV.
Targeting host rather than viral-specific factors that influence HIV replication and gene expression is one approach to reduce the likelihood of viral drug resistance. RNA interference based screens have identified a plethora of potential host targets for HIV drug development. While capping and polyadenylation are often considered to be simple default processes in eukaryotic gene expression, numerous studies have made it clear that they are deeply networked and contain HIV-specific nuances that might be considered as possible targets for therapeutic intervention. Given the significance of HIV infection in the world population, we believe that no stones that are revealed by basic science should be left unturned by those searching for novel effective treatments.
I wish to thank A. Aradi, K. Breivik, J. Brown, C. Dernell, V. Ektnitphong, J. Flatt, L. Foster, E. Gardner, A. Gonzalez, J. Guy, C. Hannum, S. Harre, S. Licholat, K. Menning, K. Neal, S. Pellow, M. Pippins, P. Simmons, L. Tauer, T. Tijoriwala, A. Walser, S. Wittstock, S. Woods and C. Zych who participated in the generation of the this review as part of an academic exercise. J.W. received support NIH grant U54 AI065357.
- Darnell JE: Reflections on the history of pre-mRNA processing and highlights of current knowledge: a unified picture. RNA. 2013, 19: 443-460. 10.1261/rna.038596.113PubMed CentralView ArticlePubMedGoogle Scholar
- Lenasi T, Barboric M: Mutual relationships between transcription and pre-mRNA processing in the synthesis of mRNA. Wiley Interdiscip Rev RNA. 2013, 4: 139-154. 10.1002/wrna.1148View ArticlePubMedGoogle Scholar
- Martinez NM, Lynch KW: Control of alternative splicing in immune responses: many regulators, many predictions, much still to learn. Immunol Rev. 2013, 253: 216-236. 10.1111/imr.12047PubMed CentralView ArticlePubMedGoogle Scholar
- Lutz CS, Moreira A: Alternative mRNA polyadenylation in eukaryotes: an effective regulator of gene expression. Wiley Interdiscip Rev RNA. 2011, 2: 22-31.View ArticlePubMedGoogle Scholar
- Cullen BR: Nuclear mRNA export: insights from virology. Trends Biochem Sci. 2003, 28: 419-424. 10.1016/S0968-0004(03)00142-7View ArticlePubMedGoogle Scholar
- Haimovich G, Medina DA, Causse SZ, Garber M, Millán-Zambrano G, Barkai O, Chávez S, Pérez-Ortín JE, Darzacq X, Choder M: Gene expression is circular: factors for mRNA degradation also foster mRNA synthesis. Cell. 2013, 153: 1000-1011. 10.1016/j.cell.2013.05.012View ArticlePubMedGoogle Scholar
- Lee JE, Lee JY, Trembly J, Wilusz J, Tian B, Wilusz CJ: The PARN deadenylase targets a discrete set of mRNAs for decay and regulates cell motility in mouse myoblasts. PLoS Genet. 2012, 8: e1002901- 10.1371/journal.pgen.1002901PubMed CentralView ArticlePubMedGoogle Scholar
- de Breyne S, Soto-Rifo R, López-Lastra M, Ohlmann T: Translation initiation is driven by different mechanisms on the HIV-1 and HIV-2 genomic RNAs. Virus Res. 2013, 171: 366-381. 10.1016/j.virusres.2012.10.006View ArticlePubMedGoogle Scholar
- Refsland EW, Harris RS: The APOBEC3 family of retroelement restriction factors. Curr Top Microbiol Immunol. 2013, 371: 1-27.PubMed CentralPubMedGoogle Scholar
- Klase Z, Houzet L, Jeang KT: MicroRNAs and HIV-1: complex interactions. J Biol Chem. 2012, 287: 40884-40890. 10.1074/jbc.R112.415448PubMed CentralView ArticlePubMedGoogle Scholar
- Tazi J, Bakkour N, Marchand V, Ayadi L, Aboufirassi A, Branlant C: Alternative splicing: regulation of HIV-1 multiplication as a target for therapeutic action. FEBS J. 2010, 277: 867-876. 10.1111/j.1742-4658.2009.07522.xView ArticlePubMedGoogle Scholar
- Suh MH, Meyer PA, Gu M, Ye P, Zhang M, Kaplan CD, Lima CD, Fu J: A dual interface determines the recognition of RNA polymerase II by RNA capping enzyme. J Biol Chem. 2010, 285: 34027-34038. 10.1074/jbc.M110.145110PubMed CentralView ArticlePubMedGoogle Scholar
- Picard-Jean F, Bougie I, Shuto S, Bisaillon M: The immunosuppressive agent mizoribine monophosphate is an inhibitor of the human RNA capping enzyme. PLoS One. 2013, 8: e54621-doi:10.1371/journal.pone.0054621PubMed CentralView ArticlePubMedGoogle Scholar
- Ghosh A, Shuman S, Lima CD: Structural insights to how mammalian capping enzyme reads the CTD code. Mol Cell. 2011, 43: 299-310. 10.1016/j.molcel.2011.06.001PubMed CentralView ArticlePubMedGoogle Scholar
- Jiao X, Chang JH, Kilic T, Tong L, Kiledjian M: A mammalian pre-mRNA 5′ end capping quality control mechanism and an unexpected link of capping to pre-mRNA processing. Mol Cell. 2013, 50: 104-115. 10.1016/j.molcel.2013.02.017PubMed CentralView ArticlePubMedGoogle Scholar
- Davidson L, Kerr A, West S: Co-transcriptional degradation of aberrant pre-mRNA by Xrn2. EMBO J. 2012, 31: 2566-2578. 10.1038/emboj.2012.101PubMed CentralView ArticlePubMedGoogle Scholar
- Viladevall L, St Amour CV, Rosebrock A, Schneider S, Zhang C, Allen JJ, Shokat KM, Schwer B, Leatherwood KH, Fisher RP: TFIIH and P-TEFb coordinate transcription with capping enzyme recruitment at specific genes in fission yeast. Mol Cell. 2009, 33: 738-751. 10.1016/j.molcel.2009.01.029PubMed CentralView ArticlePubMedGoogle Scholar
- Yang Q, Gilmartin GM, Doublié S: The structure of human cleavage factor I(m) hints at functions beyond UGUA-specific RNA binding: a role in alternative polyadenylation and a potential link to 5′ capping and splicing. RNA Biol. 2011, 8: 7487-53.View ArticleGoogle Scholar
- Flaherty SM, Fortes P, Izaurralde E, Mattaj IW, Gilmartin GM: Participation of the nuclear cap binding complex in pre-mRNA 3′ processing. Proc Natl Acad Sci U S A. 1997, 94: 11893-11898. 10.1073/pnas.94.22.11893PubMed CentralView ArticlePubMedGoogle Scholar
- Lenasi T, Peterlin BM, Barboric M: Cap-binding protein complex links pre-mRNA capping to transcription elongation and alternative splicing through positive transcription elongation factor b (P-TEFb). J Biol Chem. 2011, 286: 22758-22768. 10.1074/jbc.M111.235077PubMed CentralView ArticlePubMedGoogle Scholar
- Lenasi T, Barboric M: Mutual relationships between transcription and pre-mRNA processing in the synthesis of mRNA. Wiley Interdiscip Rev RNA. 2013, 4: 139-154. 10.1002/wrna.1148View ArticlePubMedGoogle Scholar
- Topisirovic I, Svitkin YV, Sonenberg N, Shatkin AJ: Cap and cap-binding proteins in the control of gene expression. Wiley Interdiscip Rev RNA. 2011, 2: 277-298.View ArticlePubMedGoogle Scholar
- Ling SH, Qamra R, Song H: Structural and functional insights into eukaryotic mRNA decapping. Wiley Interdiscip Rev RNA. 2011, 2: 193-208.View ArticlePubMedGoogle Scholar
- Stahla-Beek HJ, April DG, Saeedi BJ, Hannah AM, Keenan SM, Geiss BJ: Identification of a novel antiviral inhibitor of the flavivirus guanylyltransferase enzyme. J Virol. 2012, 86: 8730-8739. 10.1128/JVI.00384-12PubMed CentralView ArticlePubMedGoogle Scholar
- Ferron F, Decroly E, Selisko B, Canard B: The viral RNA capping machinery as a target for antiviral drugs. Antiviral Res. 2012, 96: 21-31. 10.1016/j.antiviral.2012.07.007View ArticlePubMedGoogle Scholar
- Ott M, Geyer M, Zhou Q: The control of HIV transcription: keeping RNA polymerase II on track. Cell Host Microbe. 2011, 10: 426-435. 10.1016/j.chom.2011.11.002PubMed CentralView ArticlePubMedGoogle Scholar
- Sanghvi VR, Steel LF: A re-examination of global suppression of RNA interference by HIV-1. PLoS One. 2011, 6: e17246-doi:10.1371/journal.pone.0017246PubMed CentralView ArticlePubMedGoogle Scholar
- Jablonski JA, Amelio AL, Giacca M, Caputi M: The transcriptional transactivator Tat selectively regulates viral splicing. Nucleic Acids Res. 2010, 38: 1249-1260. 10.1093/nar/gkp1105PubMed CentralView ArticlePubMedGoogle Scholar
- Chiu YL, Coronel E, Ho CK, Shuman S, Rana TM: HIV-1 Tat protein interacts with mammalian capping enzyme and stimulates capping of TAR RNA. J Biol Chem. 2001, 276: 12959-12966. 10.1074/jbc.M007901200View ArticlePubMedGoogle Scholar
- Chiu YL, Ho CK, Saha N, Schwer B, Shuman S, Rana TM: Tat stimulates cotranscriptional capping of HIV mRNA. Mol Cell. 2002, 10: 585-597. 10.1016/S1097-2765(02)00630-5View ArticlePubMedGoogle Scholar
- Zhou M, Deng L, Kashanchi F, Brady JN, Shatkin AJ, Kumar A: The Tat/TAR-dependent phosphorylation of RNA polymerase II C-terminal domain stimulates cotranscriptional capping of HIV-1 mRNA. Proc Natl Acad Sci USA. 2003, 100: 12666-12671. 10.1073/pnas.1835726100PubMed CentralView ArticlePubMedGoogle Scholar
- Kuciak M, Gabus C, Ivanyi-Nagy R, Semrad K, Storchak R, Chaloin O, Muller S, Mély Y, Darlix JL: The HIV-1 transcriptional activator Tat has potent nucleic acid chaperoning activities in vitro. Nucleic Acids Res. 2008, 36: 3389-3400. 10.1093/nar/gkn177PubMed CentralView ArticlePubMedGoogle Scholar
- Yang M: Discoveries of Tat-TAR interaction inhibitors for HIV-1. Curr Drug Targets Infect Disord. 2005, 5: 433-444. 10.2174/156800505774912901View ArticlePubMedGoogle Scholar
- Davidson A, Leeper TC, Athanassiou Z, Patora-Komisarska K, Karn J, Robinson JA, Varani G: Simultaneous recognition of HIV-1 TAR RNA bulge and loop sequences by cyclic peptide mimics of Tat protein. Proc Natl Acad Sci USA. 2009, 106: 11931-11936. 10.1073/pnas.0900629106PubMed CentralView ArticlePubMedGoogle Scholar
- Upert G, Di Giorgio A, Upadhyay A, Manvar D, Pandey N, Pandey VN, Patino N: Inhibition of HIV replication by cyclic and hairpin PNAs targeting the HIV-1 TAR RNA loop. J Nucleic Acids. 2012, 2012: 591025-doi:10.1155/2012/591025PubMed CentralView ArticlePubMedGoogle Scholar
- Hamasaki T, Okamoto M, Baba M: Identification of novel inhibitors of human immunodeficiency virus type 1 replication by in silico screening targeting cyclin T1/Tat interaction. Antimicrob Agents Chemother. 2013, 57: 1323-1331. 10.1128/AAC.01711-12PubMed CentralView ArticlePubMedGoogle Scholar
- Yedavalli VS, Jeang KT: Trimethylguanosine capping selectively promotes expression of Rev-dependent HIV-1 RNAs. Proc Natl Acad Sci USA. 2010, 107: 14787-14792. 10.1073/pnas.1009490107PubMed CentralView ArticlePubMedGoogle Scholar
- Dong H, Ren S, Li H, Shi PY: Separate molecules of West Nile virus methyltransferase can independently catalyze the N7 and 2′-O methylations of viral RNA cap. Virology. 2008, 377: 1-6. 10.1016/j.virol.2008.04.026PubMed CentralView ArticlePubMedGoogle Scholar
- HsuChen CC, Dubin DT: Di-and trimethylated congeners of 7-methylguanine in Sindbis virus mRNA. Nature. 1976, 264: 190-191. 10.1038/264190a0View ArticlePubMedGoogle Scholar
- van Duijn LP, Kasperaitis M, Ameling C, Voorma HO: Additional methylation at the N(2)-position of the cap of 26S semliki forest virus late mRNA and initiation of translation. Virus Res. 1986, 5: 61-66. 10.1016/0168-1702(86)90065-1View ArticlePubMedGoogle Scholar
- Jia Y, Viswakarma N, Crawford SE, Sarkar J, Sambasiva Rao M, Karpus WJ, Kanwar YS, Zhu YJ, Reddy JK: Early embryonic lethality of mice with disrupted transcription cofactor PIMT/NCOA6IP/Tgs1 gene. Mech Dev. 2012, 129: 193-207. 10.1016/j.mod.2012.08.002PubMed CentralView ArticlePubMedGoogle Scholar
- Gordon RK, Ginalski K, Rudnicki WR, Rychlewski L, Pankaskie MC, Bujnicki JM, Chiang PK: Anti-HIV-1 activity of 3-deaza-adenosine analogs. Inhibition of S-adenosylhomocysteine hydrolase and nucleotide congeners. Eur J Biochem. 2003, 270: 3507-3517. 10.1046/j.1432-1033.2003.03726.xView ArticlePubMedGoogle Scholar
- Mayers DL, Mikovits JA, Joshi B, Hewlett IK, Estrada JS, Wolfe AD, Garcia GE, Doctor BP, Burke DS, Gordon RK: Anti-human immunodeficiency virus 1 (HIV-1) activities of 3-deazaadenosine analogs: increased potency against 3′-azido-3′-deoxythymidine-resistant HIV-1 strains. Proc Natl Acad Sci U S A. 1995, 92: 215-219. 10.1073/pnas.92.1.215PubMed CentralView ArticlePubMedGoogle Scholar
- Hong JH, Kim SY, Oh CH, Yoo KH, Cho JH: Synthesis and antiviral evaluation of novel open-chain analogues of neplanocin A. Nucleosides Nucleotides Nucleic Acids. 2006, 25: 341-350. 10.1080/15257770500544578View ArticlePubMedGoogle Scholar
- Zhang H, Schinazi RF, Chu CK: Synthesis of neplanocin F analogues as potential antiviral agents. Bioorg Med Chem. 2006, 14: 8314-8322. 10.1016/j.bmc.2006.09.007View ArticlePubMedGoogle Scholar
- Vrolijk MM, Harwig A, Berkhout B, Das AT: Destabilization of the TAR hairpin leads to extension of the polyA hairpin and inhibition of HIV-1 polyadenylation. Retrovirology. 2009, 6: 13- 10.1186/1742-4690-6-13PubMed CentralView ArticlePubMedGoogle Scholar
- Soto-Rifo R, Rubilar PS, Limousin T, de Breyne S, Décimo D, Ohlmann T: DEAD-box protein DDX3 associates with eIF4F to promote translation of selected mRNAs. EMBO J. 2012, 31: 3745-3756. 10.1038/emboj.2012.220PubMed CentralView ArticlePubMedGoogle Scholar
- Soto-Rifo R, Rubilar PS, Ohlmann T: The DEAD-box helicase DDX3 substitutes for the cap-binding protein eIF4E to promote compartmentalized translation initiation of the HIV-1 genomic RNA. Nucleic Acids Res. 2013, 41: 6286-6299. 10.1093/nar/gkt306PubMed CentralView ArticlePubMedGoogle Scholar
- Mukherjee C, Patil DP, Kennedy BA, Bakthavachalu B, Bundschuh R, Schoenberg DR: Identification of cytoplasmic capping targets reveals a role for cap homeostasis in translation and mRNA stability. Cell Rep. 2012, 2: 674-684. 10.1016/j.celrep.2012.07.011PubMed CentralView ArticlePubMedGoogle Scholar
- Schrom EM, Moschall R, Schuch A, Bodem J: Regulation of retroviral polyadenylation. Adv Virus Res. 2013, 85: 1-24.View ArticlePubMedGoogle Scholar
- Shi Y, Di Giammartino DC, Taylor D, Sarkeshik A, Rice WJ, Yates JR, Frank J, Manley JL: Molecular architecture of the human pre-mRNA 3′ processing complex. Mol Cell. 2009, 33: 365-376. 10.1016/j.molcel.2008.12.028PubMed CentralView ArticlePubMedGoogle Scholar
- Palazzo AF, Akef A: Nuclear export as a key arbiter of “mRNA identity” in eukaryotes. Biochim Biophys Acta. 1819, 2012: 566-577.Google Scholar
- Tian B, Manley JL: Alternative cleavage and polyadenylation: the long and short of it. Trends Biochem Sci. 2013, 38: 312-320. 10.1016/j.tibs.2013.03.005PubMed CentralView ArticlePubMedGoogle Scholar
- Elkon R, Ugalde AP, Agami R: Alternative cleavage and polyadenylation: extent, regulation and function. Nat Rev Genet. 2013, 14: 496-506. 10.1038/nrg3482View ArticlePubMedGoogle Scholar
- Ji Z, Lee JY, Pan Z, Jiang B, Tian B: Progressive lengthening of 3′ untranslated regions of mRNAs by alternative polyadenylation during mouse embryonic development. Proc Natl Acad Sci U S A. 2009, 106: 7028-7033. 10.1073/pnas.0900028106PubMed CentralView ArticlePubMedGoogle Scholar
- Berkhout B: HIV-1 as RNA evolution machine. RNA Biol. 2011, 8: 225-229. 10.4161/rna.8.2.14801View ArticlePubMedGoogle Scholar
- An W, Telesnitsky A: Human immunodeficiency virus type 1 transductive recombination can occur frequently and in proportion to polyadenylation signal readthrough. J Virol. 2004, 78: 3419-3428. 10.1128/JVI.78.7.3419-3428.2004PubMed CentralView ArticlePubMedGoogle Scholar
- Zaiss AK, Son S, Chang LJ: RNA 3′ readthrough of oncoretrovirus and lentivirus: implications for vector safety and efficacy. J Virol. 2002, 76: 7209-7219. 10.1128/JVI.76.14.7209-7219.2002PubMed CentralView ArticlePubMedGoogle Scholar
- Brown PH, Tiley LS, Cullen BR: Efficient polyadenylation within the human immunodeficiency virus type 1 long terminal repeat requires flanking U3-specific sequences. J Virol. 1991, 65: 3340-3343.PubMed CentralPubMedGoogle Scholar
- Cherrington J, Ganem D: Regulation of polyadenylation in human immunodeficiency virus (HIV): contributions of promoter proximity and upstream sequences. EMBO J. 1992, 11: 1513-1524.PubMed CentralPubMedGoogle Scholar
- Valsamakis A, Schek N, Alwine JC: Elements upstream of the AAUAAA within the human immunodeficiency virus polyadenylation signal are required for efficient polyadenylation in vitro. Mol Cell Biol. 1992, 12: 3699-3705.PubMed CentralView ArticlePubMedGoogle Scholar
- Graveley BR, Fleming ES, Gilmartin GM: RNA structure is a critical determinant of poly(A) site recognition by cleavage and polyadenylation specificity factor. Mol Cell Biol. 1996, 16: 4942-4951.PubMed CentralView ArticlePubMedGoogle Scholar
- Graveley BR, Gilmartin GM: A common mechanism for the enhancement of mRNA 3′ processing by U3 sequences in two distantly related lentiviruses. J Virol. 1996, 70: 1612-1617.PubMed CentralPubMedGoogle Scholar
- Gilmartin GM, Fleming ES, Oetjen J, Graveley BR: CPSF recognition of an HIV-1 mRNA 3′-processing enhancer: multiple sequence contacts involved in poly(A) site definition. Genes Dev. 1995, 9: 72-83. 10.1101/gad.9.1.72View ArticlePubMedGoogle Scholar
- Gee AH, Kasprzak W, Shapiro BA: Structural differentiation of the HIV-1 polyA signals. J Biomol Struct Dyn. 2006, 23: 417-428. 10.1080/07391102.2006.10531236View ArticlePubMedGoogle Scholar
- Klasens BI, Thiesen M, Virtanen A, Berkhout B: The ability of the HIV-1 AAUAAA signal to bind polyadenylation factors is controlled by local RNA structure. Nucleic Acids Res. 1999, 27: 446-454. 10.1093/nar/27.2.446PubMed CentralView ArticlePubMedGoogle Scholar
- Zhang W, Bryson DI, Crumpton JB, Wynn J, Santos WL: Targeting folded RNA: a branched peptide boronic acid that binds to a large surface area of HIV-1 RRE RNA. Org Biomol Chem. 2013, 11: 6263-6271. 10.1039/c3ob41053fView ArticlePubMedGoogle Scholar
- Ashe MP, Griffin P, James W, Proudfoot NJ: Poly(A) site selection in the HIV-1 provirus: inhibition of promoter-proximal polyadenylation by the downstream major splice donor site. Genes Dev. 1995, 9: 3008-3025. 10.1101/gad.9.23.3008View ArticlePubMedGoogle Scholar
- McLaren M, Asai K, Cochrane A: A novel function for Sam68: enhancement of HIV-1 RNA 3′ end processing. RNA. 2004, 10: 1119-1129. 10.1261/rna.5263904PubMed CentralView ArticlePubMedGoogle Scholar
- Knoepfel SA, Abad A, Abad X, Fortes P, Berkhout B: Design of modified U1i molecules against HIV-1 RNA. Antiviral Res. 2012, 94: 208-216. 10.1016/j.antiviral.2012.03.010View ArticlePubMedGoogle Scholar
- Sajic R, Lee K, Asai K, Sakac D, Branch DR, Upton C, Cochrane A: Use of modified U1 snRNAs to inhibit HIV-1 replication. Nucleic Acids Res. 2007, 35: 247-255. 10.1093/nar/gkl869PubMed CentralView ArticlePubMedGoogle Scholar
- Scott JM, Imperiale MJ: Promoter-proximal poly(A) sites are processed efficiently, but the RNA products are unstable in the nucleus. Mol Cell Biol. 1997, 17: 2127-2135.PubMed CentralView ArticlePubMedGoogle Scholar
- Andersen PK, Lykke-Andersen S, Jensen TH: Promoter-proximal polyadenylation sites reduce transcription activity. Genes Dev. 2012, 26: 2169-2179. 10.1101/gad.189126.112PubMed CentralView ArticlePubMedGoogle Scholar
- Valente ST, Gilmartin GM, Venkatarama K, Arriagada G, Goff SP: HIV-1 mRNA 3′ end processing is distinctively regulated by eIF3f, CDK11, and splice factor 9G8. Mol Cell. 2009, 36: 279-289. 10.1016/j.molcel.2009.10.004PubMed CentralView ArticlePubMedGoogle Scholar
- Hori T, Takeuchi H, Saito H, Sakuma R, Inagaki Y, Yamaoka S: A carboxy-terminally truncated human CPSF6 lacking residues encoded by exon 6 inhibits HIV-1 cDNA synthesis and promotes capsid disassembly. J Virol. 2013, 87: 7726-7736. 10.1128/JVI.00124-13PubMed CentralView ArticlePubMedGoogle Scholar
- Fricke T, Valle-Casuso JC, White TE, Brandariz-Nuñez A, Bosche WJ, Reszka N, Gorelick R, Diaz-Griffero F: The ability of TNPO3-depleted cells to inhibit HIV-1 infection requires CPSF6. Retrovirology. 2013, 10: 46- 10.1186/1742-4690-10-46PubMed CentralView ArticlePubMedGoogle Scholar
- Price AJ, Fletcher AJ, Schaller T, Elliott T, Lee K, KewalRamani VN, Chin JW, Towers GJ, James LC: CPSF6 defines a conserved capsid interface that modulates HIV-1 replication. PLoS Pathog. 2012, 8: e1002896-10.1371/journal.ppat.1002896PubMed CentralView ArticlePubMedGoogle Scholar
- de la Vega L, Sánchez-Duffhues G, Fresno M, Schmitz ML, Muñoz E, Calzado MA: The 73 kDa subunit of the CPSF complex binds to the HIV-1 LTR promoter and functions as a negative regulatory factor that is inhibited by the HIV-1 Tat protein. J Mol Biol. 2007, 372: 317-330. 10.1016/j.jmb.2007.06.075View ArticlePubMedGoogle Scholar
- Calzado MA, Sancho R, Muñoz E: Human immunodeficiency virus type 1 Tat increases the expression of cleavage and polyadenylation specificity factor 73-kilodalton subunit modulating cellular and viral expression. J Virol. 2004, 78: 6846-6854. 10.1128/JVI.78.13.6846-6854.2004PubMed CentralView ArticlePubMedGoogle Scholar
- Zhang Z, Klatt A, Henderson AJ, Gilmour DS: Transcription termination factor Pcf11 limits the processivity of Pol II on an HIV provirus to repress gene expression. Genes Dev. 2007, 21: 1609-1614. 10.1101/gad.1542707PubMed CentralView ArticlePubMedGoogle Scholar
- Mouland AJ, Coady M, Yao XJ, Cohen EA: Hypophosphorylation of poly(A) polymerase and increased polyadenylation activity are associated with human immunodeficiency virus type 1 Vpr expression. Virology. 2002, 292: 321-330. 10.1006/viro.2001.1261View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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.