E138K and M184I mutations in HIV-1 reverse transcriptase coemerge as a result of APOBEC3 editing in the absence of drug exposure

Fourati, Slim; Malet, Isabelle; Lambert, Sidonie; Soulié, Cathia; Wirden, Marc; Flandre, Philippe; Fofana, Djeneba Bocar; Sayon, Sophie; Simon, Anne; Katlama, Christine; Cálvez, Vincent; Marcelin, Anne–Geneviève

doi:10.1097/qad.0b013e3283560703

Cited by 43 publications

(40 citation statements)

References 25 publications

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“…These prevalence rates are similar to those observed in other in vitro studies that analyzed the emergence of G-to-A nucleotide mutations in other regions of the HIV-1 genome (11,12,14,16,18,19). Similarly, in MDM, 81.A-Vif K22E generated a pool of G-to-A nucleotide mutations encoding G15R, G17S, G24E, and G28R (Fig.…”

Section: Hiv-1 Vif Mutants and Overall Sequence Diversity In V3supporting

confidence: 71%

“…However, the activity of Vif against APOBEC3G/F is not absolute. Indeed, some Vif mutants fail (to different extents) to neutralize these enzymes (2,(10)(11)(12)(13). For instance, previous in vitro studies showed that in the presence of the Vif amino acid substitution K22E, Vif completely loses the ability to neutralize APOBEC3G (implying APOBEC3G editing of the viral genome) and retains partial activity against APOBEC3F (implying less editing of APOBEC3F than APOBEC3G).…”

mentioning

confidence: 99%

“…In the presence of other HIV-1 variants with suboptimal Vif activity, the limited APOBEC3G/F-driven editing may also contribute to genetic diversity and thus benefit the virus by facilitating escape from other antiretroviral drugs (such as rilpivirine or thymidine analogues) and also cellular immunity (11,12,(15)(16)(17)(18)(19). HIV-1 sequences carrying the genetic footprints of past deamination events have been detected in treated and untreated chronically infected patients (20,21), vertically infected infants (22), and long-term nonprogressors (23), suggesting that variations in Vif activity against APOBEC3G/F can occur in many different clinical settings.…”

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confidence: 99%

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Incomplete APOBEC3G/F Neutralization by HIV-1 Vif Mutants Facilitates the Genetic Evolution from CCR5 to CXCR4 Usage

Alteri

Surdo

Bellocchi

et al. 2015

Antimicrob Agents Chemother

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APOBEC3G/F proteins are packaged into HIV-1 virions and associate with the reverse transcription (RT) complex. There, they deaminate cytosine residues to uracil in the single-stranded DNA minus strand, resulting in proviral guanosine-to-adenosine (Gto-A) nucleotide mutations in the plus-strand DNA (6, 7). These mutations predominantly occur in a GG or GA dinucleotide context, which are the preferential (but not exclusive) target sites for APOBEC3G and APOBEC3F, respectively (2, 6). Previous studies have shown that the frequency of G-to-A nucleotide mutations increases over the genome in the 5=-to-3= direction, with the lowest frequency in the 5= long terminal repeat and the highest in the 5= portion of the nef gene sequence (6). Beyond G-to-A mutations, C-to-T nucleotide mutations in plus-strand DNA have also been described (6).The activity of APOBEC3G/F is generally counteracted by the HIV-1 regulatory protein Vif by promoting proteasome-dependent APOBEC3G/F degradation (8) and inhibiting packaging in the producer cell (9). However, the activity of Vif against APOBEC3G/F is not absolute. Indeed, some Vif mutants fail (to different extents) to neutralize these enzymes (2, 10-13). For instance, previous in vitro studies showed that in the presence of the Vif amino acid substitution K22E, Vif completely loses the ability to neutralize APOBEC3G (implying APOBEC3G editing of the viral genome) and retains partial activity against APOBEC3F (implying less editing of APOBEC3F than APOBEC3G). In the presence of the Vif amino acid substitution E45G, Vif retained weak activity against APOBEC3G (implying a low rate of APOBEC3G editing) and completely neutralized APOBEC3F activity (implying no or limited APOBEC3F editing) (2).Previous studies have shown that these two Vif amino acid substitutions can facilitate the emergence of the G-to-A mutation

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Section: Hiv-1 Vif Mutants and Overall Sequence Diversity In V3supporting

confidence: 71%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Incomplete APOBEC3G/F Neutralization by HIV-1 Vif Mutants Facilitates the Genetic Evolution from CCR5 to CXCR4 Usage

Alteri

Surdo

Bellocchi

et al. 2015

Antimicrob Agents Chemother

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“…The host factors APOBEC3F and APOBEC3G induce G-to-A substitutions in reverse-transcribed nascent retroviral DNA (70). G-to-A hypermutations play an important role in the evolution of antiretroviral drug resistance (71,72) and could be associated with ART failure (73). The extent of G-to-A hypermutations is not associated with levels of HIV-1 RNA (74), although hypermutations are frequent in viremic controllers (75).…”

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confidence: 99%

Long-Range HIV Genotyping Using Viral RNA and Proviral DNA for Analysis of HIV Drug Resistance and HIV Clustering

et al. 2015

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HIV genotyping is a critical tool for antiviral drug resistance testing that has revolutionized HIV care and advanced HIVrelated research. Routine antiretroviral (ARV) drug resistance testing is useful in choosing an optimal treatment regimen and monitoring its efficiency in clinical practice (1-12). HIV genotyping has been used successfully in research on HIV transmission clusters and HIV transmission dynamics (13-35).Initial broadly used ARV regimens included combinations of nucleoside reverse transcriptase (RT) inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). To monitor the emergence of drug resistance mutations associated with NRTIs and NNRTIs, HIV genotyping targeted viral sequences spanning an approximately 1,000-to 1,300-bp region of the HIV-1 genome encoding viral protease and partial RT, using viral RNA as a template for amplification. While the RNA-based approach works well in antiretroviral therapy (ART)-naive individuals, it is less successful if levels of viral replication are low, such as in individuals on ART. The sequence length of traditional RNAbased HIV genotyping for drug resistance is relatively short and does not cover the HIV-1 region encoding viral integrase or the viral envelope, hindering analysis of drug resistance mutations associated with integrase strand transfer inhibitors or entry inhibitors. The global scale up of ARV treatment and successful introduction of integrase strand transfer inhibitors and entry inhibitors into clinical trials and clinical practice necessitate modification of traditional methods of HIV genotyping.Two commercial genotyping assays, ViroSeq HIV-1 from Abbott Molecular and TruGene HIV-1 from Siemens Molecular Diagnostics, have been widely used for analysis of HIV-1-associated drug resistance. Both genotyping kits were extensively tested and validated (36)(37)(38)(39)(40)(41)(42)(43)(44)(45). While the ViroSeq HIV-1 kit is still on the market, Siemens discontinued selling and supporting the TruGene HIV-1 kit in 2014. The ViroSeq HIV-1 kit covers the entire protease-coding region and the RT region encoding the first 320 amino acids. The TruGene HIV-1 sequences span the protease (amino acids 4 to 99)-and RT (amino acids 40 to 240)-coding regions. The CDC supplies WHO-designated and CDC-supported President's Emergency Plan for AIDS Relief (PEPFAR) Genotyping Laboratories with the ATCC HIV-1 Drug Resistance Genotyping kit (46) for drug resistance testing. Many experienced genotyping laboratories have developed their own in-house amplification and sequencing protocols (11,(47)(48)(49)(50)(51)(52)(53)(54)(55)(56), including identification of minor viral variants that are normally missed by commercial genotyping kits (57-61). All of these approaches generally include smaller and more restricted regions for testing HIV-1 drug resistance.Recently, the protocol developed by Gall et al. (62)

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“…Although it can be hypothesized that more-sensitive sequencing techniques may suffer from interference by these hypermutated defective sequences, to our knowledge, the risk of falsely identifying resistance mutations in DNA as a consequence of hypermutation has not yet been demonstrated. On the contrary, it has been suggested that sublethal activity of APOBEC3 proteins and the resulting increasing number of G-to-A transitions may facilitate the emergence of drug resistance (48)(49)(50). We provide clear evidence that detection of the PR mutations D30N and M46I and the RT mutations E138K, M184I, and G190E may result from the presence of hypermutated HIV DNA sequences and that identification and clearance of deep sequencing reads with evidence of hypermutation are difficult.…”

Section: Discussionmentioning

confidence: 86%

Deep Sequencing of HIV-1 RNA and DNA in Newly Diagnosed Patients with Baseline Drug Resistance Showed No Indications for Hidden Resistance and Is Biased by Strong Interference of Hypermutation

et al. 2016

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Deep sequencing of plasma RNA or proviral DNA may be an interesting alternative to population sequencing for the detection of baseline transmitted HIV-1 drug resistance. Using a Roche 454 GS Junior HIV-1 prototype kit, we performed deep sequencing of the HIV-1 protease and reverse transcriptase genes on paired plasma and buffy coat samples from newly diagnosed HIV-1-positive individuals. Selection was based on the outcome of population sequencing and included 12 patients with either a revertant amino acid at codon 215 of the reverse transcriptase or a singleton resistance mutation, 4 patients with multiple resistance mutations, and 4 patients with wild-type virus. Deep sequencing of RNA and DNA detected 6 and 43 mutations, respectively, that were not identified by population sequencing. A subsequently performed hypermutation analysis, however, revealed hypermutation in 61.19% of 3,188 DNA reads with a resistance mutation. The removal of hypermutated reads dropped the number of additional mutations in DNA from 43 to 17. No hypermutation evidence was found in the RNA reads. Five of the 6 additional RNA mutations and all additional DNA mutations, after full exclusion of hypermutation bias, were observed in the 3 individuals with multiple resistance mutations detected by population sequencing. Despite focused selection of patients with T215 revertants or singleton mutations, deep sequencing failed to identify the resistant T215Y/F or M184V or any other resistance mutation, indicating that in most of these cases there is no hidden resistance and that the virus detected at diagnosis by population sequencing is the original infecting variant.A nalyzing the presence of transmitted drug resistance mutations (TDRMs) after diagnosis of HIV-1 infection is the standard of care in most developed countries (1). Information on TDRMs allows clinicians to initiate the first-line regimen with the highest likelihood of virological response. Surveys revealed TDRM prevalences of approximately 10% in Europe, a number that has remained relatively stable over the last few years, although some shifts in affected drug classes have been reported (2). The most commonly observed TDRMs in Europe and North America are associated with resistance to nucleoside reverse transcriptase (RT) inhibitors (NRTIs) or nonnucleoside RT inhibitors (NNRTIs). Baseline resistance to protease inhibitors (PIs) is less prevalent (2, 3). Standard baseline resistance testing is still mainly performed using Sanger-based population sequencing. This method generally fails to detect mutants representing less than 20% of the viral population (4, 5).Resistant viruses that initially caused the infection may be overgrown, with time and in the absence of drugs, by fitter variants that lack all or part of the resistance mutations as a result of back mutation (6-11). The highest rates of disappearance have been recorded for the NRTI mutation M184V/I (11-13) and for the thymidine analogue-associated mutations K70R and T215Y (11). Back mutation may result in replacement of the...

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E138K and M184I mutations in HIV-1 reverse transcriptase coemerge as a result of APOBEC3 editing in the absence of drug exposure

Cited by 43 publications

References 25 publications

Incomplete APOBEC3G/F Neutralization by HIV-1 Vif Mutants Facilitates the Genetic Evolution from CCR5 to CXCR4 Usage

Incomplete APOBEC3G/F Neutralization by HIV-1 Vif Mutants Facilitates the Genetic Evolution from CCR5 to CXCR4 Usage

Long-Range HIV Genotyping Using Viral RNA and Proviral DNA for Analysis of HIV Drug Resistance and HIV Clustering

Deep Sequencing of HIV-1 RNA and DNA in Newly Diagnosed Patients with Baseline Drug Resistance Showed No Indications for Hidden Resistance and Is Biased by Strong Interference of Hypermutation

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