Human APOBEC3G Can Restrict Retroviral Infection in Avian Cells and Acts Independently of both UNG and SMUG1

Langlois, Marc‐André; Neuberger, Michael S.

doi:10.1128/jvi.02469-07

Cited by 48 publications

(47 citation statements)

References 54 publications

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“…1 and 2 demonstrated that the recruitment of UNG2 into virions was directly responsible for influencing HIV-1 mutation, we then decided to reevaluate the real influence of UNG2 incorporation into HIV-1 particles on virus infectivity. First, the contradictory results reported in the literature about the impact of UNG2 on HIV-1 infectivity and replication (9,17,18,22,37,40,48) were further challenged using a single-round infection assay for the investigation of virus infectivity when UNG2 was overexpressed in either virus-producing cells or target cells. Wild-type reporter viruses carrying the gene encoding GFP were produced in 293T cells overexpressing the HA-tagged form of UNG2, and equivalent amounts of virus, as measured by HIV-1 CAp24 in ELISA, were used to assay virus infectivity on HeLa cells stably expressing the CD4 receptor (HeLa-CD4).…”

Section: Resultsmentioning

confidence: 99%

Recruitment of the Nuclear Form of Uracil DNA Glycosylase into Virus Particles Participates in the Full Infectivity of HIV-1

Guenzel

Hérate

Rouzic

et al. 2012

J Virol

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The HIV-1 Vpr protein participates in the early steps of the virus life cycle by influencing the accuracy of reverse transcription. This role of Vpr was related to the recruitment of the nuclear form of the uracil DNA glycosylase (UNG2) enzyme into virus particles, but several conflicting findings have been reported regarding the role of UNG2 encapsidation on viral infectivity. Here, we report that the catalytic activity of UNG2 was not required for influencing HIV-1 mutation, and this function of UNG2 was mapped within a 60-amino-acid domain located in the N-terminal region of the protein required for direct interaction with the p32 subunit of the replication protein A (RPA) complex. Importantly, enforced recruitment of overexpressed UNG2 into virions resulted in a net increase of virus infectivity, and this positive effect on infectivity was also independent of the UNG2 enzymatic activity. In contrast, virus infectivity and replication, as well as the efficiency of the viral DNA synthesis, were significantly reduced when viruses were produced from cells depleted of either endogenous UNG2 or RPA p32. Taken together, these results demonstrate that incorporation of UNG2 into virions has a positive impact on HIV-1 infectivity and replication and positively influences the reverse transcription process through a nonenzymatic mechanism involving the p32 subunit of the RPA complex.

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Section: Resultsmentioning

confidence: 99%

Recruitment of the Nuclear Form of Uracil DNA Glycosylase into Virus Particles Participates in the Full Infectivity of HIV-1

Guenzel

Hérate

Rouzic

et al. 2012

J Virol

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“…One well-characterized mechanism is the enzymatic deamination of cytosine in the minus strand of HIV-1 cDNA by members of the APOBEC3 subfamily (APOBEC3D, -F, -G, and -H) to generate C/G→U/A transition mutations after plus strand synthesis (43,44). This deamination mechanism leads to lethal hypermutation of the viral genome and potent restriction of viral infection, but there are conflicting reports as to whether UNG2 excision of uracils is part of the restriction mechanism (45)(46)(47). In contrast, the dUTP-mediated mechanism elaborated here results in nonmutagenic incorporation of uracil on both strands of the viral DNA and requires hUNG2 to prevent viral integration.…”

Section: Discussionmentioning

confidence: 99%

Uracil DNA glycosylase initiates degradation of HIV-1 cDNA containing misincorporated dUTP and prevents viral integration

Weil

Ghosh²,

Zhou

et al. 2013

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

119

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Significance Misincorporation of dUTP into DNA is detrimental to eukaryotes, prokaryotes, and viruses. This study reveals the fate of uracilated HIV-1 DNA in human cells. Early stages of the viral life cycle are unaffected, but integration of uracilated viral DNA into the host genome is prevented. This effect is wholly dependent on the presence of UNG2, a nuclear enzyme that excises uracil from DNA. This study establishes that UNG2 is a restriction factor for uracilated HIV-1 DNA and explains why this pathway is not fully engaged in CD4+ T cells and macrophages.

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“…First, it may subject the cDNA to DNA repair pathways that could ultimately degrade the viral genome, although it is unclear if classic base excision repair pathways play a role (40). Second, the introduction of deoxyuridine can compromise integration into the host genome (41).…”

Section: Loop Graft Variants Effectively Restrict Hiv-bhagwat and Co-mentioning

confidence: 99%

Local Sequence Targeting in the AID/APOBEC Family Differentially Impacts Retroviral Restriction and Antibody Diversification

Kohli

Maul

Guminski

et al. 2010

Journal of Biological Chemistry

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Nucleic acid cytidine deaminases of the activation-induced deaminase (AID)/APOBEC family are critical players in active and innate immune responses, playing roles as target-directed, purposeful mutators. AID specifically deaminates the host immunoglobulin (Ig) locus to evolve antibody specificity, whereas its close relative, APOBEC3G (A3G), lethally mutates the genomes of retroviral pathogens such as HIV. Understanding the basis for the target-specific action of these enzymes is essential, as mistargeting poses significant risks, potentially promoting oncogenesis (AID) or fostering drug resistance (A3G). AID prefers to deaminate cytosine in WRC (W ‫؍‬ A/T, R ‫؍‬ A/G) motifs, whereas A3G favors deamination of CCC motifs. This specificity is largely dictated by a single, divergent protein loop in the enzyme family that recognizes the DNA sequence. Through grafting of this substrate-recognition loop, we have created enzyme variants of A3G and AID with altered local targeting to directly evaluate the role of sequence specificity on immune function. We find that grafted loops placed in the A3G scaffold all produced efficient restriction of HIV but that foreign loops in the AID scaffold compromised hypermutation and class switch recombination. Local targeting, therefore, appears alterable for innate defense against retroviruses by A3G but important for adaptive antibody maturation catalyzed by AID. Notably, AID targeting within the Ig locus is proportionally correlated to its in vitro ability to target WRC sequences rather than non-WRC sequences. Although other mechanisms may also contribute, our results suggest that local sequence targeting by AID/APOBEC3 enzymes represents an elegant example of co-evolution of enzyme specificity with its target DNA sequence.

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Human APOBEC3G Can Restrict Retroviral Infection in Avian Cells and Acts Independently of both UNG and SMUG1

Cited by 48 publications

References 54 publications

Recruitment of the Nuclear Form of Uracil DNA Glycosylase into Virus Particles Participates in the Full Infectivity of HIV-1

Recruitment of the Nuclear Form of Uracil DNA Glycosylase into Virus Particles Participates in the Full Infectivity of HIV-1

Uracil DNA glycosylase initiates degradation of HIV-1 cDNA containing misincorporated dUTP and prevents viral integration

Local Sequence Targeting in the AID/APOBEC Family Differentially Impacts Retroviral Restriction and Antibody Diversification

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