Basis for Early and Preferential Selection of the E138K Mutation in HIV-1 Reverse Transcriptase

McCallum, Matthew; Oliveira, Maureen; Ibanescu, Ruxandra-Ilinca; Kramer, Victor G.; Moïsi, Daniela; Asahchop, Eugene L.; Brenner, Bluma G.; Harrigan, P. Richard; Xu, Hongtao; Wainberg, Mark A.

doi:10.1128/aac.01029-13

Cited by 21 publications

(20 citation statements)

References 45 publications

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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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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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“…However, these results do not rule out a minor role for other APOBEC3 proteins, such as, e.g., APOBEC3A (monocytes/macrophages only), APOBEC3B, APOBEC3C, APOBEC3DE, and/or APOBEC3H haplotypes II, V, and VII (34,(36)(37)(38)(39)(40)(41)(42) and/or a contribution from RT and/or RNA Pol II (34,(43)(44)(45). The activity of APOBEC3A differs from that of other deaminases because it exerts its antiviral effect in monocyte/macrophage producer cells (46) and may be targeted by Vpx (47) but does not restrict HIV-1 replication in the target cell (48).…”

Section: Figmentioning

confidence: 84%

“…In contrast, GAA-to-AAA mutations did occur 16% more often than average GA-to-AA mutations and may therefore have been induced by APOBEC3F or other deaminases (e.g., APOBEC3A [monocytes/macrophages only], APOBEC3B, APOBEC3C, APOBEC3DE, and/or APOBEC3H haplotypes II, V, and VII) (34,(36)(37)(38)(39)(40)(41)(42) or a combination of several deaminases, with contributions from RT and/or RNA Pol II (34,(43)(44)(45) (Fig. 2C and D).…”

Section: Apobec3 and Hiv-1 Evolution In Natural Infectionmentioning

confidence: 99%

Possible Footprints of APOBEC3F and/or Other APOBEC3 Deaminases, but Not APOBEC3G, on HIV-1 from Patients with Acute/Early and Chronic Infections

Armitage

Deforche

Welch

et al. 2014

J Virol

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Members of the apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like-3 (APOBEC3) innate cellular cytidine deaminase family, particularly APOBEC3F and APOBEC3G, can cause extensive and lethal G-to-A mutations in HIV-1 plusstrand DNA (termed hypermutation). It is unclear if APOBEC3-induced mutations in vivo are always lethal or can occur at sublethal levels that increase HIV-1 diversification and viral adaptation to the host. The viral accessory protein Vif counteracts APOBEC3 activity by binding to APOBEC3 and promoting proteasome degradation; however, the efficiency of this interaction varies, since a range of hypermutation frequencies are observed in HIV-1 patient DNA. Therefore, we examined "footprints" of APOBEC3G and APOBEC3F activity in longitudinal HIV-1 RNA pol sequences from approximately 3,000 chronically infected patients by determining whether G-to-A mutations occurred in motifs that were favored or disfavored by these deaminases. Gto-A mutations were more frequent in APOBEC3G-disfavored than in APOBEC3G-favored contexts. In contrast, mutations in APOBEC3F-disfavored contexts were relatively rare, whereas mutations in contexts favoring APOBEC3F (and possibly other deaminases) occurred 16% more often than average G-to-A mutations. These results were supported by analyses of >500 HIV-1 env sequences from acute/early infection. IMPORTANCECollectively, our results suggest that APOBEC3G-induced mutagenesis is lethal to HIV-1, whereas mutagenesis caused by APOBEC3F and/or other deaminases may result in sublethal mutations that might facilitate viral diversification. Therefore, Vifspecific cytotoxic T lymphocyte (CTL) responses and drugs that manipulate the interplay between Vif and APOBEC3 may have beneficial or detrimental clinical effects depending on how they affect the binding of Vif to various members of the APOBEC3 family.

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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: 85%

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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Basis for Early and Preferential Selection of the E138K Mutation in HIV-1 Reverse Transcriptase

Cited by 21 publications

References 45 publications

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

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

Possible Footprints of APOBEC3F and/or Other APOBEC3 Deaminases, but Not APOBEC3G, on HIV-1 from Patients with Acute/Early and Chronic Infections

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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