APOBEC-mediated viral restriction: not simply editing?

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

doi:10.1016/j.tibs.2007.01.004

Cited by 258 publications

(245 citation statements)

References 103 publications

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“…Thus, APOBEC proteins are defined as a collection of related polynucleotide (RNA/DNA) cytidine deaminases. Each APOBEC protein contains one or two copies (A3G has two) of a cytidine deaminase (CDA) domain that is distinguished be the presence of a signature His/Cys-X-Glu-X 23-28 -Pro-Cys-X 2 -Cys motif: in some cases the CDA domain has deaminase activity, whereas in others it does not (discussed below) Conticello et al 2005;Holmes et al 2007b;Chiu & Greene 2008). With respect to the likely mechanism of catalysis, the histidine and two cysteine residues are thought to coordinate a zinc ion that enables the catalytic glutamic acid to deprotonate a water molecule and generate the zinc hydroxide nucleophile that is necessary for the deamination of the pyrimidine ring of cytidine (Betts et al 1994;.…”

Section: Apobec3g Catalyses Cytidine Deamination Of Hiv-1 Dnamentioning

confidence: 99%

“…There are many instances of inhibitory effects on infection and transposition, as well as the induction of DNA mutations, and much of this work is summarized elsewhere (Chen et al 2006;Holmes et al 2007b;Chiu & Greene 2008;Vartanian et al 2008). Nevertheless, there is still a great deal to be understood regarding these APOBECpathogen/parasite interactions including: the determinants of substrate specificity for particular APOBEC proteins, mechanisms of inhibition (editing and editing-independent effects), mechanisms and routes of evasion, and assessments of the physiological significance of these interactions in the context of animal hosts (rather than in cultured cell experiments).…”

Section: Anti-hiv-1 Phenotypes Of Diverse Human Apobec Proteinsmentioning

confidence: 99%

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APOBEC proteins and intrinsic resistance to HIV-1 infection

Malim

2008

Phil. Trans. R. Soc. B

243

268

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Members of the APOBEC family of cellular polynucleotide cytidine deaminases, most notably APOBEC3G and APOBEC3F, are potent inhibitors of HIV-1 infection. Wild type HIV-1 infections are largely spared from APOBEC3G/F function through the action of the essential viral protein, Vif. In the absence of Vif, APOBEC3G/F are encapsidated by budding virus particles leading to excessive cytidine (C) to uridine (U) editing of negative sense reverse transcripts in newly infected cells. This registers as guanosine (G) to adenosine (A) hypermutations in plus-stranded cDNA. In addition to this profoundly debilitating effect on genetic integrity, APOBEC3G/F also appear to inhibit viral DNA synthesis by impeding the translocation of reverse transcriptase along template RNA. Because the functions of Vif and APOBEC3G/F proteins oppose each other, it is likely that fluctuations in the Vif–APOBEC balance may influence the natural history of HIV-1 infection, as well as viral sequence diversification and evolution. Given Vif's critical role in suppressing APOBEC3G/F function, it can be argued that pharmacologic strategies aimed at restoring the activity of these intrinsic anti-viral factors in the context of infected cells in vivo have clear therapeutic merit, and therefore deserve aggressive pursuit.

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Section: Apobec3g Catalyses Cytidine Deamination Of Hiv-1 Dnamentioning

confidence: 99%

Section: Anti-hiv-1 Phenotypes Of Diverse Human Apobec Proteinsmentioning

confidence: 99%

APOBEC proteins and intrinsic resistance to HIV-1 infection

Malim

2008

Phil. Trans. R. Soc. B

243

268

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“…Four of the seven APOBEC3 molecules identified in humans (APOBEC3B, APOBEC3DE, APOBEC3F, and APOBEC3G) inhibit HIV replication to a varying degree (1,4). HIV-1, by means of its Vif protein, counteracts the antiviral activity of APOBEC3G, APOBEC3F, and APOBEC3DE (5-9) by promoting proteasome-dependent degradation (6) and inhibiting packaging (10) in the producer cell.…”

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confidence: 99%

“…The mechanisms underlying APOBEC3-mediated HIV-1 restriction are a combination of editing (11) and nonediting activities (4). In the absence of a functional HIV-1 Vif, the budding virion, incorporates different APOBEC3 family members (e.g., APOBEC3G or APOBEC3F), which then deaminate cytosines of the newly synthesized cDNA minus strand during reverse transcription (RT) in the next cycle of infection (3,12,13).…”

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confidence: 99%

Cytidine deamination induced HIV-1 drug resistance

Mulder

Harari²,

Simon³

2008

Proc. Natl. Acad. Sci. U.S.A.

148

169

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The HIV-1 Vif protein is essential for overcoming the antiviral activity of DNA-editing apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3 (APOBEC3) cytidine deaminases. We show that naturally occurring HIV-1 Vif point mutants with suboptimal anti-APOBEC3G activity induce the appearance of proviruses with lamivudine (3TC) drug resistance-associated mutations before any drug exposure. These mutations, ensuing from cytidine deamination events, were detected in >40% of proviruses with partially defective Vif mutants. Transfer of drug resistance from hypermutated proviruses via recombination allowed for 3TC escape under culture conditions prohibitive for any WT viral growth. These results demonstrate that defective hypermutated genomes can shape the phenotype of the circulating viral population. Partially active Vif alleles resulting in incomplete neutralization of cytoplasmic APOBEC3 molecules are directly responsible for the generation of a highly diverse, yet G-to-A biased, proviral reservoir, which can be exploited by HIV-1 to generate viable and drug-resistant progenies.hypermutation ͉ reservoir ͉ diversity ͉ reverse transcription

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“…Incorporated A3G specifically deaminates cytosine residues to uracil in growing singlestranded DNA during reverse transcription, leading to HIV genome degradation or hypermutation (5,25,39,48,49,98). More recent studies indicate that deaminase-independent mechanisms might also be involved in antiviral activity of A3 (4,27,28,30,54,61). The amount of encapsidated A3G in wild-type (wt) HIV-1 virions is dramatically reduced by a Vifdependent degradation via the ubiquitination-proteasome pathway (50,79,94,95).…”

mentioning

confidence: 99%

Restriction of Equine Infectious Anemia Virus by Equine APOBEC3 Cytidine Deaminases

Zielonka

Bravo²,

Marino

et al. 2009

J Virol

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The mammalian APOBEC3 (A3) proteins comprise a multigene family of cytidine deaminases that act as potent inhibitors of retroviruses and retrotransposons. The A3 locus on the chromosome 28 of the horse genome contains multiple A3 genes: two copies of A3Z1, five copies of A3Z2, and a single copy of A3Z3, indicating a complex evolution of multiple gene duplications. We have cloned and analyzed for expression the different equine A3 genes and examined as well the subcellular distribution of the corresponding proteins. Additionally, we have tested the functional antiretroviral activity of the equine and of several of the human and nonprimate A3 proteins against the Equine infectious anemia virus (EIAV), the Simian immunodeficiency virus (SIV), and the Adeno-associated virus type 2 (AAV-2). Hematopoietic cells of horses express at least five different A3s: A3Z1b, A3Z2a-Z2b, A3Z2c-Z2d, A3Z2e, and A3Z3, whereas circulating macrophages, the natural target of EIAV, express only part of the A3 repertoire. The five A3Z2 tandem copies arose after three consecutive, recent duplication events in the horse lineage, after the split between Equidae and Carnivora. The duplicated genes show different antiviral activities against different viruses: equine A3Z3 and A3Z2c-Z2d are potent inhibitors of EIAV while equine A3Z1b, A3Z2a-Z2b, A3Z2e showed only weak anti-EIAV activity. Equine A3Z1b and A3Z3 restricted AAV and all equine A3s, except A3Z1b, inhibited SIV. We hypothesize that the horse A3 genes are undergoing a process of subfunctionalization in their respective viral specificities, which might provide the evolutionary advantage for keeping five copies of the original gene.The Equine infectious anemia virus (EIAV) (family Retroviridae, genus Lentivirus) infects equids almost worldwide, causing a persistent infection characterized by recurring viremia, fever, thrombocytopenia, and wasting symptoms (40). EIAV infections are used as a model for natural immunologic control of lentivirus replication and virus persistence and as a test system to improve vaccines against lentiviruses (10,40,41,82). In vivo EIAV replicates predominantly in macrophages (77). Interaction with the equine lentiviral receptor 1 (ELR1) has been demonstrated to be responsible for EIAV internalization (96). There have been no reported cases of EIAV infections in humans, suggesting that it is an intrinsically safe virus and of interest for use in a clinical setting. Therefore, EIAV-based lentiviral vectors for human gene therapy were recently developed (1, 67, 68).In the last few years, two cellular proteins that inhibit many different retroviruses have been characterized: tripartite motif protein 5 alpha (TRIM5␣) and apolipoprotein B mRNAediting enzyme-catalytic polypeptide 3 (APOBEC3 [A3]) (for a review, see reference 92). With respect to TRIM5␣ proteins, both human and nonhuman primate TRIM5␣ orthologues can restrict infection by EIAV (26,72). The activity of equine TRIM5␣ on EIAV infection, however, has not been described so far. With respect to A3 proteins...

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APOBEC-mediated viral restriction: not simply editing?

Cited by 258 publications

References 103 publications

APOBEC proteins and intrinsic resistance to HIV-1 infection

APOBEC proteins and intrinsic resistance to HIV-1 infection

Cytidine deamination induced HIV-1 drug resistance

Restriction of Equine Infectious Anemia Virus by Equine APOBEC3 Cytidine Deaminases

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