APOBEC-Mediated Editing of Viral RNA

Bishop, Kate N.; Holmes, Rebecca K.; Sheehy, Ann M.; Malim, Michael H.

doi:10.1126/science.1100658

Cited by 235 publications

(238 citation statements)

References 8 publications

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“…[36][37][38][39] Rat APOBEC1 (rA1) was selected, because a recent report has demonstrated that this deaminase restricts HIV propagation and can edit HIV RNA. 16 Southern blot analysis confirmed that A3F suppressed viral DNA levels, albeit to a lesser extent than A3G (Fig. 8).…”

Section: Resultsmentioning

confidence: 65%

“…Cytomegalovirus promoter (CMV)-driven expression vectors coding for human A3G, A3F, and rat A1 have been described elsewhere. 8,15,16 A3G-HA is a CMV-driven expression vector encoding A3G fused with a hemagglutinin fusion epitope tag at its carboxy-terminal end. A3G-HA was constructed via polymerase chain reaction (PCR) amplification of A3G complementary DNA from a hepatocyte complementary DNA library using forward primer 5Ј-TAAGC-GGAATTCATGAAGCCTCACTTCAGAAACACA-GTGG-3Ј and reverse primer 5Ј-TAGAAGCTCGA-GTCAAGCGTAATCTGGAACATCGTATGGATAG TTTTCCTGATTCTGCAG-3Ј.…”

Section: Methodsmentioning

confidence: 99%

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APOBEC-mediated interference with hepadnavirus production

et al. 2005

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APOBEC3G is a cellular cytidine deaminase displaying broad antiretroviral activity. Recently, it was shown that APOBEC3G can also suppress hepatitis B virus (HBV) production in human hepatoma cells. In the present study, we characterized the mechanisms of APO-BEC-mediated antiviral activity against HBV and related hepadnaviruses. We show that human APOBEC3G blocks HBV production in mammalian and nonmammalian cells and is active against duck HBV as well. Early steps of viral morphogenesis, including RNA and protein synthesis, binding of pregenomic RNA to core protein, and self-assembly of viral core protein, were unaffected. However, APOBEC3G rendered HBV core protein-associated full-length pregenomic RNA nuclease-sensitive. Ongoing reverse-transcription in capsids that had escaped the block in morphogenesis was not significantly inhibited. The antiviral effect was not modulated by abrogating or enhancing expression of the accessory HBV X protein, suggesting that HBV X protein does not represent a functional homologue to the HIV vif protein. Furthermore, human APOBEC3F but not rat APOBEC1 inhibited HBV DNA production. Viral RNA and low-level DNA produced in the presence of APOBEC3F or rat APOBEC1 occasionally displayed mutations, but the majority of clones were wild-type. In conclusion, APOBEC3G and APOBEC3F but not rat APOBEC1 can downregulate the production of replication-competent hepadnaviral nucleocapsids. In contrast to HIV and other retroviruses, however, APOBEC3G/3F-mediated editing of nucleic acids does not seem to represent an effective innate defense mechanism for hepadnaviruses. H epadnaviruses are a group of small enveloped DNA viruses with a narrow host range and a relative tropism for the liver. Hepatitis B virus (HBV), the prototypic member of the hepadnavirus family, is a major cause of liver disease worldwide, ranging from acute and chronic hepatitis to cirrhosis and hepatocellular carcinoma. 1,2 Other members of the family include the duck hepatitis B virus (DHBV) and the woodchuck hepatitis virus. 3,4 Hepadnaviral replication involves reverse-transcription of a pregenomic RNA (pgRNA) intermediate inside nucleocapsids, which are formed by 180 or 240 core protein subunits. Inside the capsid, the viral polymerase converts pgRNA into minus-strand DNA, which in turn is completed to a double-stranded, relaxed circular DNA molecule. 5,6 This life cycle places HBV into the large family of retroelements, which all require reverse-transcription of an RNA intermediate.Recently, a cellular defense mechanism targeting a wide range of retroviruses was identified. It was shown that the propagation of HIV-1 strains lacking the accessory protein Vif is suppressed in a number of nonpermissive cells and that this block was due to expression of the cytidine deaminase APOBEC3G (A3G). 7,8 Further studies revealed that A3G induces massive C3 U deamination of single stranded retroviral DNA, resulting in DNA degradation or lethal G3 A hypermutation. [9][10][11] Interestingly, A3G can also interfere with the HBV life c...

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Section: Resultsmentioning

confidence: 65%

Section: Methodsmentioning

confidence: 99%

APOBEC-mediated interference with hepadnavirus production

et al. 2005

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“…6A and D), suggesting that the observed nucleotide changes were induced by A1. Given that rat A1 is also known to edit retroviral RNA, we looked at cDNA extracted from A1 WT -expressing RSCs at 8 hpi at an MOI of 0.01 for evidence of additional deaminase activities (8). Similar to the DNA sequencing results, G3A and C3T transitions in viral cDNA were observed, with the majority of clones containing 1 mutation, while clones with 2 or 3 mutations were also observed ( Fig.…”

Section: Rat Model For Survival Of Encephalitis With Intracranial Hsvmentioning

confidence: 66%

“…A1 homologues are putative inducers of mutations in retrovirus DNA and also in DNA of A1-expressing bacteria (8,24,29,44,49). Thus, to investigate the mechanism of the A1-dependent inhibition of HSV-1 gene expression, we looked at the potential editing of HSV-1 viral DNA.…”

Section: Rat Model For Survival Of Encephalitis With Intracranial Hsvmentioning

confidence: 99%

APOBEC1-Mediated Editing and Attenuation of Herpes Simplex Virus 1 DNA Indicate That Neurons Have an Antiviral Role during Herpes Simplex Encephalitis

Gee

Ando

Kitayama

et al. 2011

J Virol

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APOBEC1 (A1) is a cytidine deaminase involved in the regulation of lipids in the small intestine. Herpes simplex virus 1 (HSV-1) is a ubiquitous pathogen that is capable of infecting neurons in the brain, causing encephalitis. Here, we show that A1 is induced during encephalitis in neurons of rats infected with HSV-1. In cells stably expressing A1, HSV-1 infection resulted in significantly reduced virus replication compared to that in control cells. Infectivity could be restored to levels comparable to those observed for control cells if A1 expression was silenced by specific A1 short hairpin RNAs (shRNA). Moreover, cytidine deaminase activity appeared to be essential for this inhibition and led to an impaired accumulation of viral mRNA transcripts and DNA copy numbers. The sequencing of viral gene UL54 DNA, extracted from infected A1-expressing cells, revealed G-to-A and C-to-T transitions, indicating that A1 associates with HSV-1 DNA. Taken together, our results demonstrate a model in which A1 induction during encephalitis in neurons may aid in thwarting HSV-1 infection.The human apolipoprotein B-editing catalytic polypeptide (ABOBEC) family is a group of zinc-dependent DNA and RNA cytidine deaminases and consists of AID, APOBEC1 (A1), APOBEC2 (A2), seven APOBEC3s (APOBEC3A [A3A] to A3H), and APOBEC4 (A4). A1, the first APOBEC to be discovered, is known to introduce a premature stop codon into host apolipoprotein B mRNA in the gastrointestinal tract, an event critical for lipid metabolism (17,40,61). The editing by A1 is highly precise and specifically converts C to U at position 6666 of the apolipoprotein B mRNA substrate (46). Along with APOBEC1 complementation factor (ACF), these two proteins constitute the minimal required components necessary for the editing of apolipoprotein B mRNA in vitro (37).Cytidine deaminases first came into the limelight as antiviral factors after A3G was identified as a cellular restriction factor capable of inhibiting HIV-1 dissemination in the absence of HIV-1 virus infectivity factor (Vif) (56). This molecule was later shown to inhibit retrovirus infection by inducing a massive hypermutation of the murine leukemia virus (MLV) genome (23). Further detailed studies revealed that APOBEC molecules are packaged into HIV-1 virions in virus producer cells via a specific interaction with Gag and viral RNA and then exert their deaminase activity in subsequent target cells on a single-stranded DNA (ssDNA) intermediate synthesized by reverse transcriptase (3, 28, 55). Editing can lead to nonsynonymous mutations, such as premature stop codons, in critical proteins (e.g., reverse transcriptase) necessary for virus replication and infectivity, severely impairing the next round of infection (54,64). Extensive studies to assess the antiviral nature of these APOBEC enzymes have been performed across a broad range of retroviruses and hepatitis B virus (HBV) (7,35,36,42,43,50,56,58).Herpes simplex virus (HSV) is an enveloped, double-stranded DNA (dsDNA) virus and a member of the genus Alphaherpe...

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“…In contrast, RNAediting mechanism (besides those the snoRNA-based base modifications) in other eukaryotes, prokaryotes, and viruses do not make use of RNA components [210,30]. Models for the evolution of the gRNA-based editing process are discussed in [223], a phylogenetic analysis of U-insertion editing [224] suggests that extensive editing is a primitive genetic phenomenon that has disappeared in more modern organism, see also [376].…”

Section: Other Classes Of Small Ncrnamentioning

confidence: 99%

Evolutionary patterns of non-coding RNAs

Bompfünewerer

Flamm

Fried

et al. 2005

Theory in Biosciences

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A plethora of new functions of non-coding RNAs have been discovered in past few years. In fact, RNA is emerging as the central player in cellular regulation, taking on active roles in multiple regulatory layers from transcription, RNA maturation, and Manuscript January 2005RNA modification to translational regulation. Nevertheless, very little is known about the evolution of this "Modern RNA World" and its components. In this contribution we attempt to provide at least a cursory overview of the diversity of non-coding RNAs and functional RNA motifs in non-translated regions of regular messenger RNAs (mRNAs) with an emphasis on evolutionary questions. This survey is complemented by an in-depth analysis of examples from different classes of RNAs focusing mostly on their evolution in the vertebrate lineage. We present a survey of Y RNA genes in vertebrates, studies of the molecular evolution of the U7 snRNA, the snoRNAs E1/U17, E2, and E3, the Y RNA family, the let-7 microRNA family, and the mRNA-like evf-1 gene. We furthermore discuss the statistical distribution of microRNAs in metazoans, which suggests an explosive increase in the microRNA repertoire in vertebrates. The analysis of the transcription of non-coding RNAs (ncRNAs) suggests that small RNAs in general are genetically mobile in the sense that their association with a hostgene (e.g. when transcribed from introns of a mRNA) can change on evolutionary time scales. The let-7 family demonstrates, that even the mode of transcription (as intron or as exon) can change among paralogous ncRNA.

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APOBEC-Mediated Editing of Viral RNA

Cited by 235 publications

References 8 publications

APOBEC-mediated interference with hepadnavirus production

APOBEC-mediated interference with hepadnavirus production

APOBEC1-Mediated Editing and Attenuation of Herpes Simplex Virus 1 DNA Indicate That Neurons Have an Antiviral Role during Herpes Simplex Encephalitis

Evolutionary patterns of non-coding RNAs

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