Patient HIV-1 strains carrying the multiple nucleoside resistance mutations are cross-resistant to abacavir

Laethem, Kristel Van; Witvrouw, Myriam; Balzarini, Jan; Schmit, Jean-Claude; Sprecher, S; Hermans, Philippe; Leal, Manuel; Harrer, Thomas; Ruiz, Lı́dia; Clotet, Bonaventura; Ranst, Marc Van; Desmyter, Jan; Clercq, Erik De; Vandamme, Anne‐Mieke

doi:10.1097/00002030-200003100-00027

Cited by 26 publications

(12 citation statements)

References 7 publications

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“…The NNRTIs are non-competitive inhibitors of HIV-1 RT that bind to a hydrophobic pocket, which is located in the palm of p66 subunit of RT close to the polymerase active site [39]. The two side chains rotate away from the hydrophobic pocket and point toward the polymerase active site, resulting in an inactive form [41]. Binding of an NNRTI to RT induces conformational changes in the dNTP-binding pocket within p66.…”

Section: Nnrtismentioning

confidence: 99%

Mechanism of HIV antiretroviral drugs progress toward drug resistance

Ammaranond

Sanguansittianan

2011

Fundamemntal Clinical Pharma

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The rapid replication rate of HIV-1 RNA and its inherent genetic variation have led to the production of many HIV-1 variants with decreased drug susceptibility. The capacity of HIV to develop drug resistance mutations is a major obstacle to long-term effective anti-HIV therapy. Incomplete suppression of viral replication with an initial drug regimen diminishes the clinical benefit to the patient and may promote the development of broader drug resistance that may cause subsequent treatment regimens to be ineffective. The increased clinical use of combination antiretroviral treatment for HIV-1 infection has led to the selection of viral strains resistant to multiple drugs, including strains resistant to all licensed nucleoside analog RT inhibitors and protease inhibitors. Therefore, it is important to understand the influence of such mutations on viral properties such as replicative fitness, fidelity, and mutation rates. Although research continues to improve our understanding of resistance, leading to refined treatment strategies and, in some cases, improved outcome, resistance to antiretroviral therapy remains a major cause of treatment failure among patients living with HIV-1.

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Section: Nnrtismentioning

confidence: 99%

Mechanism of HIV antiretroviral drugs progress toward drug resistance

Ammaranond

Sanguansittianan

2011

Fundamemntal Clinical Pharma

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“…This mutation develops in up to 5% of patients who receive dual NRTI therapy with didanosine in combination with zidovudine or stavudine (49,181,285,323,335,338,390). Q151M alone causes intermediate levels of resistance to zidovudine, didanosine, zalcitibine, stavudine, and abacavir (168,342,350,389). Q151M is generally followed by mutations at positions 62, 75, 77, and 116.…”

Section: Multinucleoside Resistance Due To Q151mmentioning

confidence: 99%

“…Like many of the PI and NRTI resistance mutations, some of the NNRTI resistance mutations may also compromise virus replication. Two mechanisms of impaired replication have been proposed: changes in the conformation of the dNTP binding pocket (194,389) and changes in RNase H activity (4,112).…”

Section: Nnrti Resistance Mutationsmentioning

confidence: 99%

Genotypic Testing for Human Immunodeficiency Virus Type 1 Drug Resistance

2002

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There are 16 approved human immunodeficiency virus type 1 (HIV-1) drugs belonging to three mechanistic classes: protease inhibitors, nucleoside and nucleotide reverse transcriptase (RT) inhibitors, and nonnucleoside RT inhibitors. HIV-1 resistance to these drugs is caused by mutations in the protease and RT enzymes, the molecular targets of these drugs. Drug resistance mutations arise most often in treated individuals, resulting from selective drug pressure in the presence of incompletely suppressed virus replication. HIV-1 isolates with drug resistance mutations, however, may also be transmitted to newly infected individuals. Three expert panels have recommended that HIV-1 protease and RT susceptibility testing should be used to help select HIV drug therapy. Although genotypic testing is more complex than typical antimicrobial susceptibility tests, there is a rich literature supporting the prognostic value of HIV-1 protease and RT mutations. This review describes the genetic mechanisms of HIV-1 drug resistance and summarizes published data linking individual RT and protease mutations to in vitro and in vivo resistance to the currently available HIV drugs

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“…These mutations were also selected in vivo, except that the codon Y115F mutation is only rarely observed in patient samples (6,17). Additionally, abacavir resistance has been observed for two patterns selected by other nucleoside analogues, which are associated with NRTI multidrug resistance (MDR), the Q151 M complex (24) and the family of amino acid insertions between codons 67 and 70 of the reverse transcriptase (14). Furthermore, abacavir resistance has been described in the context of zidovudine and lamivudine resistance: M184V was selected after in vitro passage of a zidovudine-resistant viral clone in the presence of abacavir (23), and in some clinical isolates an increase in abacavir resistance was observed after M184V had developed in the context of zidovudine resistance (6).…”

mentioning

confidence: 99%

Prediction of Abacavir Resistance from Genotypic Data: Impact of Zidovudine and Lamivudine Resistance In Vitro and In Vivo

Walter

Schmidt

Werwein

et al. 2002

Antimicrob Agents Chemother

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Abacavir is frequently used in antiretroviral combination therapies as a potent nucleoside reverse transcriptase inhibitor (NRTI). Four mutations are selected for by abacavir in vitro and in vivo: K65R, L74V, Y115F, and M184V. Abacavir resistance has also been observed in NRTI multidrug-resistant samples. Furthermore, abacavir resistance has been described in the context of zidovudine resistance. To evaluate the genetic basis of abacavir resistance, the viral genotype and phenotypic resistance were analyzed for 307 patient samples. Lowand high-level resistances were defined as 2.5-to 5.5-fold-and >5.5-fold-reduced susceptibility, respectively. If all samples with abacavir-selected and NRTI multidrug resistance-associated mutations were scored as resistant, 27.6% of the samples were misclassified, mainly due to samples falsely scored as susceptible. Therefore, the relative frequencies of other mutations were evaluated. Mutations at codons 44 and 118 were rarely detected in abacavir-susceptible samples but were overrepresented in resistant samples. Site-directed mutagenesis of E44D, V118I, and M184V resulted in low-level resistance for the double mutant 44/184 and the triple mutant. Low-level abacavir resistance was also detected for a viral clone carrying zidovudine mutations only. Additional insertion of M184V into the zidovudine background doubled the resistance, whereas 44/118 did not lead to a further increase. Incorporating combinations of zidovudine mutations and M184V into the scoring system markedly reduced the number of misclassified samples, whereas 44/118 did not improve the prediction. In conclusion, the combination of M184V with zidovudine mutations gives rise to high-level abacavir resistance, which may be clinically relevant. Thus, options for useful sequential combinations of NRTI are limited.

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Patient HIV-1 strains carrying the multiple nucleoside resistance mutations are cross-resistant to abacavir

Cited by 26 publications

References 7 publications

Mechanism of HIV antiretroviral drugs progress toward drug resistance

Mechanism of HIV antiretroviral drugs progress toward drug resistance

Genotypic Testing for Human Immunodeficiency Virus Type 1 Drug Resistance

Prediction of Abacavir Resistance from Genotypic Data: Impact of Zidovudine and Lamivudine Resistance In Vitro and In Vivo

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