DNA Deamination Mediates Innate Immunity to Retroviral Infection

Harris, Reuben S.; Bishop, Kate N.; Sheehy, Ann M.; Craig, Heather M.; Petersen-Mahrt, Svend K.; Watt, Ian N.; Neuberger, Michael S.; Malim, Michael H.

doi:10.1016/s0092-8674(03)00423-9

Cited by 1,182 publications

(648 citation statements)

References 22 publications

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“…Accordingly, it was demonstrated that the expression of A3G in virus-producing cells yields A3G-containing progeny virions (vif-deficient HIV-1 or murine leukaemia virus, MLV ) that, following infection of fresh cells, produce reverse transcripts that are littered with guanosine (G) to adenosine (A) transition mutations on the plus (second) strand (figure 3; Harris et al 2003a;Mangeat et al 2003;Mariani et al 2003;Zhang et al 2003). Because the frequency of mutation can exceed 10 per cent of all G residues, this phenomenon is often called hypermutation.…”

Section: Apobec3g Catalyses Cytidine Deamination Of Hiv-1 Dnamentioning

confidence: 99%

APOBEC proteins and intrinsic resistance to HIV-1 infection

Malim

2008

Phil. Trans. R. Soc. B

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239

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%

APOBEC proteins and intrinsic resistance to HIV-1 infection

Malim

2008

Phil. Trans. R. Soc. B

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239

268

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“…Human APOBEC3G (hA3G) belongs to a family of cytidine deaminases and is a broadly acting antiviral restriction factor (1,2). In addition to inhibiting the replication of Vif-deficient HIV-1, hA3G has been shown to inhibit the replication of other exogenous retroviruses, endogenous retroviruses, retrotransposons, and hepatitis B virus (3)(4)(5)(6)(7)(8)(9)(10)(11)(12).…”

Section: Ells Have Evolved Numerous Strategies To Restrict Infectionmentioning

confidence: 99%

Resistance of human T cell leukemia virus type 1 to APOBEC3G restriction is mediated by elements in nucleocapsid

Derse

Hill

Princler

et al. 2007

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

113

118

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Human T cell leukemia virus type 1 (HTLV-1) has evolved a remarkable strategy to thwart the antiviral effects of the cellular cytidine deaminase APOBEC3G (hA3G). HTLV-1 infects T lymphocytes in vivo, where, like HIV-1, it is likely to encounter hA3G. HIV-1 counteracts the innate antiviral activity of hA3G by producing an accessory protein, Vif, which hastens the degradation of hA3G. In contrast, HTLV-1 does not encode a Vif homologue; instead, HTLV-1 has evolved a cis-acting mechanism to prevent hA3G restriction. We demonstrate here that a peptide motif in the C terminus of the HTLV-1 nucleocapsid (NC) domain inhibits hA3G packaging into nascent virions. Mutation of amino acids within this region resulted in increased levels of hA3G incorporation into virions and increased susceptibility to hA3G restriction. Elements within the C-terminal extension of the NC domain are highly conserved among the primate T cell leukemia viruses, but this extension is absent in all other retroviral NC proteins.

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“…The defective virions are competent to enter target cells and to synthesize full-length double stranded viral DNA; however, most of this DNA fails to integrate and few proviruses are generated (8,17,18). The viral DNA contained numerous G 3 A mutations caused by deamination of minus-strand cytosines to uracil (18)(19)(20)(21)(22). In cells infected with wild-type HIV-1, little APOBEC3G was encapsidated into the virions, and G 3 A mutations in the viral reverse transcripts were rare (18,23,24).…”

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confidence: 99%

A single amino acid of APOBEC3G controls its species-specific interaction with virion infectivity factor (Vif)

Schröfelbauer

Chen

Landau

2004

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

298

305

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The virion infectivity factor (Vif) accessory protein of HIV-1 forms a complex with the cellular cytidine deaminase APOBEC3G (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G) to block its antiviral activity. The antiviral property of APOBEC3G is conserved in several mammalian species, but the ability of Vif to block this activity is species-specific. HIV-1 Vif blocks human APOBEC3G but does not block the mouse or African green monkey (AGM) enzyme. Conversely, SIVAGM Vif blocks the antiviral activity of AGM but not human APOBEC3G. We demonstrate that the species specificity is caused by a single amino acid difference in APOBEC3G. Replacement of Asp-128 in human APOBEC3G with the Lys-128 of AGM APOBEC3G caused the enzyme to switch its interaction, becoming sensitive to SIVAGM Vif and resistant to HIV-1 Vif. Conversely, the reciprocal Lys to Asp switch in AGM APOBEC3G reversed its specificity for Vif. The reversal of biological activity was accompanied by the corresponding switch in the species specificity with which the enzyme physically associated with Vif and was excluded from virions. The charge of the amino acid at position 128 was a critical determinant of species specificity. Based on the crystal structure of the distantly related Escherichia coli cytidine deaminase, we propose that this amino acid is positioned on a solvent-exposed loop of APOBEC3G on the same face of the protein as the catalytic site.

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DNA Deamination Mediates Innate Immunity to Retroviral Infection

Cited by 1,182 publications

References 22 publications

APOBEC proteins and intrinsic resistance to HIV-1 infection

APOBEC proteins and intrinsic resistance to HIV-1 infection

Resistance of human T cell leukemia virus type 1 to APOBEC3G restriction is mediated by elements in nucleocapsid

A single amino acid of APOBEC3G controls its species-specific interaction with virion infectivity factor (Vif)

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