Population Level Analysis of Human Immunodeficiency Virus Type 1 Hypermutation and Its Relationship with APOBEC3G and
            <i>vif</i>
            Genetic Variation

Pace, Craig; Keller, Jean; Nolan, David; James, Ian; Gaudieri, Silvana; Moore, Crystal Dea; Mallal, S.

doi:10.1128/jvi.00888-06

Cited by 118 publications

(99 citation statements)

References 44 publications

(45 reference statements)

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“…Ultimately, the importance of understanding the cellular regulation of A3G gene expression is underscored by clinical observations that correlate elevated A3G expression with either the ability to resist HIV-1 exposure or successfully control infection (18,20,47). These novel insights into regulation of A3G expression may lay the molecular foundation for development of therapeutics aimed at exploiting and manipulating the A3G regulatory circuit allowing for modulation of A3G to protective levels in vivo.…”

Section: Discussionmentioning

confidence: 99%

NFAT and IRF Proteins Regulate Transcription of the Anti-HIV Gene, APOBEC3G

Farrow

Kim

Wolinsky

et al. 2011

Journal of Biological Chemistry

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The human cytidine deaminase APOBEC3G (A3G) is an innate restriction factor that inhibits human immunodeficiency virus, type 1 (HIV-1) replication. Regulation of A3G gene expression plays an important role in this suppression. Currently, an understanding of the mechanism of this gene regulation is largely unknown. Here, we have identified and characterized a TATA-less core promoter with an NFAT/ IRF-4 composite binding site that confers cell type-specific transcriptional regulation. We found that A3G expression is critically dependent on NFATc1/NFATc2 and IRF-4. When either NFATc1 or NFATc2 and IRF-4 were co-expressed, A3G promoter activity was observed in cells that normally lack A3G expression and expression was not detected in the presence of the individual factors. This induced A3G expression allowed normally permissive CEMss cells to adopt a nonpermissive state, able to resist an HIV-1⌬vif challenge. This represents the first reporting of manipulating the restrictive state of a cell type via gene regulation. Identification of NFAT and IRF family members as critical regulators of A3G expression offers important insight into the transcriptional control mechanisms that regulate innate immune responses and identifies specific targets for therapeutic intervention aimed at effectively boosting our natural immunity, in the form of a host defensive factor, against HIV-1.Human A3G is an innate immune resistance factor for a broad range of retroviruses. The gene is expressed in hematopoietic cell populations, lymphoid tissues, and selected established T cell lines (1). The A3G protein restricts human immunodeficiency virus, type 1 (HIV-1) 2 infection by accessing the budding virion and disrupting the reverse transcription of HIV-1 RNA in target cells. The post-entry block impairs initiation (2), inhibits transcript elongation (3), and induces Gto-A hypermutation in the nascent viral cDNA through cytidine deamination (4 -7). HIV-1 Vif potently counteracts this restriction in the producer cell by targeting A3G to the proteasome, thereby preventing incorporation of A3G into the virus particle (8 -11). The mechanism for producer cell mediated A3G restriction and HIV-1 Vif counteraction have been extensively studied and characterized (12) and the Vif:A3G regulatory circuit is one of the most interesting examples of how cellular restriction factors participate in the exertion of a powerful intracellular defense mechanism.A3G mRNA and protein levels vary across both developmental and differentiation transitions, and these differences influence the restrictive capacity of the particular cell type. Decreased A3G expression and susceptibility to HIV-1 occurs during differentiation of human monocytes to monocyte-derived macrophages (13). Conversely, increased A3G expression with enhanced resistance to HIV-1 occurs during dendritic cell maturation (14). Finally, decreased levels of A3G have been noted in the CD4 ϩ T helper 2 (Th2) subset, compared with T helper 1 (Th1) cells (15). Taken together, these observations suggest that ...

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Section: Discussionmentioning

confidence: 99%

NFAT and IRF Proteins Regulate Transcription of the Anti-HIV Gene, APOBEC3G

Farrow

Kim

Wolinsky

et al. 2011

Journal of Biological Chemistry

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“…A third possibility is genetic variation among individuals, and polymorphisms in A3G or cullin5 have been correlated with differences in the rates of disease progression . Finally, though not addressing cause versus effect, increased CD4 T-cell counts and decreased virus loads have each been correlated with the burden of hypermutated (inactivated) HIV-1 sequences (Pace et al 2006;Land et al 2008). It is worth noting, however, that not only does a good deal of controversy remain concerning the conclusions of some of these studies (Do et al 2005;Gandhi et al 2008) but also unambiguously establishing causality for these in vivo phenotypes can be expected to be challenging.…”

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

confidence: 99%

“…The consensus dinucleotide target for deamination is also different with 5 0 -TC (substrate cytidine underlined) serving as the preferred site for A3F (Bishop et al 2004a;Liddament et al 2004;Wiegand et al 2004), rather than the 5 0 -CC defined for A3G ( §5). Numerous analyses of HIV-1 sequences recovered from HIV-1 infected persons reveal the frequent presence of G-to-A hypermutated viral DNA ( Fitzgibbon et al 1993;Vartanian et al 1994;Janini et al 2001;Kieffer et al 2005;Pace et al 2006;Kijak et al 2008;Land et al 2008). Further inspection of the local sequence context of such mutations reveals 5 0 -GG (plus sense sequence) as the predominant target and 5 0 -GA as the second most likely substrate.…”

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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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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“…However, even in the presence of Vif, there is evidence of A3 deaminations inducing hypermutation of integrated proviral genomes (16)(17)(18)(19)(20)(21)(22)(23). There are two ways in which this occurs.…”

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confidence: 99%

“…More detailed analysis of the signatures revealed that A3G is most active at a 5=CCC motif, and A3D can be differentiated from A3F and A3H by examining a larger surrounding sequence 3= of the cytosine (30). Studies that sequenced integrated proviral genomes have shown that proviral DNAs contain mutations in multiple sequence contexts, suggesting that multiple A3s can mutate the same genome (16)(17)(18)(19)(20)(21)(22)(23). However, what was unable to be concluded from these studies was if the mutations induced from multiple A3s occurred in a single round of replication or multiple rounds of replication.…”

mentioning

confidence: 99%

Mechanism of Enhanced HIV Restriction by Virion Coencapsidated Cytidine Deaminases APOBEC3F and APOBEC3G

Ara

Love

Follack

et al. 2017

J Virol

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The APOBEC3 (A3) enzymes, A3G and A3F, are coordinately expressed in CD4 ϩ T cells and can become coencapsidated into HIV-1 virions, primarily in the absence of the viral infectivity factor (Vif). A3F and A3G are deoxycytidine deaminases that inhibit HIV-1 replication by inducing guanine-to-adenine hypermutation through deamination of cytosine to form uracil in minus-strand DNA. The effect of the simultaneous presence of both A3G and A3F on HIV-1 restriction ability is not clear. Here, we used a single-cycle infectivity assay and biochemical analyses to determine if coencapsidated A3G and A3F differ in their restriction capacity from A3G or A3F alone. Proviral DNA sequencing demonstrated that compared to each A3 enzyme alone, A3G and A3F, when combined, had a coordinate effect on hypermutation. Using size exclusion chromatography, rotational anisotropy, and in vitro deamination assays, we demonstrate that A3F promotes A3G deamination activity by forming an A3F/G hetero-oligomer in the absence of RNA which is more efficient at deaminating cytosines. Further, A3F caused the accumulation of shorter reverse transcripts due to decreasing reverse transcriptase efficiency, which would leave singlestranded minus-strand DNA exposed for longer periods of time, enabling more deamination events to occur. Although A3G and A3F are known to function alongside each other, these data provide evidence for an A3F/G hetero-oligomeric A3 with unique properties compared to each individual counterpart.IMPORTANCE The APOBEC3 enzymes APOBEC3F and APOBEC3G act as a barrier to HIV-1 replication in the absence of the HIV-1 Vif protein. After APOBEC3 enzymes are encapsidated into virions, they deaminate cytosines in minus-strand DNA, which forms promutagenic uracils that induce transition mutations or proviral DNA degradation. Even in the presence of Vif, footprints of APOBEC3-catalyzed deaminations are found, demonstrating that APOBEC3s still have discernible activity against HIV-1 in infected individuals. We undertook a study to better understand the activity of coexpressed APOBEC3F and APOBEC3G. The data demonstrate that an APOBEC3F/ APOBEC3G hetero-oligomer can form that has unique properties compared to each APOBEC3 alone. This hetero-oligomer has increased efficiency of virus hypermutation, raising the idea that we still may not fully realize the antiviral mechanisms of endogenous APOBEC3 enzymes. Hetero-oligomerization may be a mechanism to increase their antiviral activity in the presence of Vif.

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Population Level Analysis of Human Immunodeficiency Virus Type 1 Hypermutation and Its Relationship with APOBEC3G and vif Genetic Variation

Cited by 118 publications

References 44 publications

NFAT and IRF Proteins Regulate Transcription of the Anti-HIV Gene, APOBEC3G

NFAT and IRF Proteins Regulate Transcription of the Anti-HIV Gene, APOBEC3G

APOBEC proteins and intrinsic resistance to HIV-1 infection

Mechanism of Enhanced HIV Restriction by Virion Coencapsidated Cytidine Deaminases APOBEC3F and APOBEC3G

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