G→A Hypermutation in Protease and Reverse Transcriptase Regions of Human Immunodeficiency Virus Type 1 Residing in Resting CD4
            <sup>+</sup>
            T Cells In Vivo

Kieffer, Tara L.; Kwon, Patty; Nettles, Richard E.; Han, Yefei; Ray, Stuart C.; Siliciano, Robert F.

doi:10.1128/jvi.79.3.1975-1980.2005

Cited by 157 publications

(181 citation statements)

References 38 publications

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“…Because the underlying mechanism is cytidine deamination in the target cell, the extensive accumulation of resistant genomes is rapid, but independent, of drug exposure. Lastly, our findings recapitulated very well the spectrum, the positions of G-to-A mutations, and the high frequency of M184I detected in RT sequences derived from resting CD4 ϩ T lymphocytes of highly active antiretroviral therapy (HAART)-treated patients (21).…”

Section: Hiv-1 Vif Mutants Lead To the Accumulation Of 3tc-resistant supporting

confidence: 75%

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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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Section: Hiv-1 Vif Mutants Lead To the Accumulation Of 3tc-resistant supporting

confidence: 75%

“…Indeed, HIV-1 sequences carrying the genetic footprints of past deamination have been detected in treated and untreated chronically infected patients (20)(21)(22), vertically infected infants (23), and long-term nonprogressors (18,24) suggesting that variations in HIV-1 Vif's anti-APOBEC3 activity occur in many different clinical settings.…”

mentioning

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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“…S2), which is consistent with other reports [5,6,10,13]. A small proportion of sequences had stop codons not obviously due to G-to-A hypermutation (average 3%, range 0-12%) .…”

Section: Hypermutated Sequences Are Frequent In Hiv-1 Reservoirssupporting

confidence: 81%

“…Many defective proviruses have large internal deletions [7,8]. Defective proviruses are also the result of APOBEC editing, which induces G-to-A hypermutation [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Establishment and stability of the latent HIV-1 DNA reservoir

Brodin

Zanini

Thebo

et al. 2016

Preprint

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HIV-1 infection currently cannot be cured because the virus persists as integrated proviral DNA in long-lived cells despite years of suppressive antiretroviral therapy (ART). To characterize establishment, turnover, and evolution of viral DNA reservoirs we deep-sequenced the p17gag region of the HIV-1 genome from samples obtained from 10 patients after 3-18 years of suppressive ART. For each of these patients, whole genome deep-sequencing data of HIV-1 RNA populations before onset of ART were available from 6-12 longitudinal plasma samples spanning 5-8 years of untreated infection. This enabled a detailed analysis of the dynamics and origin of proviral DNA during ART. A median of 14% (range 0-42%) of the p17gag DNA sequences were overtly defective due to G-to-A hypermutation. The remaining sequences were remarkably similar to previously observed RNA sequences and showed no evidence of evolution over many years of suppressive ART. Most sequences from the DNA reservoirs were very similar to viruses actively replicating in plasma (RNA sequences) shortly before start of ART. The results do not support persistent HIV-1 replication as a mechanism to maintain the HIV-1 reservoir during suppressive therapy. Rather, the data indicate that viral DNA variants are turning over as long as patients are untreated and that suppressive ART halts this turnover.

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“…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

245

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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G→A Hypermutation in Protease and Reverse Transcriptase Regions of Human Immunodeficiency Virus Type 1 Residing in Resting CD4 ⁺ T Cells In Vivo

Cited by 157 publications

References 38 publications

Cytidine deamination induced HIV-1 drug resistance

Cytidine deamination induced HIV-1 drug resistance

Establishment and stability of the latent HIV-1 DNA reservoir

APOBEC proteins and intrinsic resistance to HIV-1 infection

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G→A Hypermutation in Protease and Reverse Transcriptase Regions of Human Immunodeficiency Virus Type 1 Residing in Resting CD4 + T Cells In Vivo

Cited by 157 publications

References 38 publications

Cytidine deamination induced HIV-1 drug resistance

Cytidine deamination induced HIV-1 drug resistance

Establishment and stability of the latent HIV-1 DNA reservoir

APOBEC proteins and intrinsic resistance to HIV-1 infection

Contact Info

Product

Resources

About

G→A Hypermutation in Protease and Reverse Transcriptase Regions of Human Immunodeficiency Virus Type 1 Residing in Resting CD4 ⁺ T Cells In Vivo