Presence of M184I/V in minor HIV‐1 populations of patients with lamivudine and/or didanosine treatment failure

Svedhem, Veronica; Bergroth, Tobias; Lidman, Knut; Sönnerborg, Anders

doi:10.1111/j.1468-1293.2007.00502.x

Cited by 5 publications

(9 citation statements)

References 21 publications

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“…As expected [13,15], SPCR detected the M184V mutants in all samples that were positive by direct sequencing. In samples lacking M184I/V or with different proportions of the mutants in the plasma and CSF viruses, it must be emphasized that these results could have been influenced by the relatively low HIV‐1 RNA load found in some samples.…”

Section: Discussionsupporting

confidence: 86%

Difference in drug resistance patterns between minor HIV‐1 populations in cerebrospinal fluid and plasma

et al. 2009

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ObjectiveThe aim of the study was to determine to what extent unique drug resistance patterns appear in minor and major HIV-1 quasispecies in cerebrospinal fluid (CSF) as compared with blood. MethodsForty-four plasma and CSF samples from 13 multi-treatment-experienced patients, seven of whom provided longitudinal samples, were included in the study. The subjects had failed antiretroviral therapy including lamivudine. The reverse transcriptase (RT) gene was examined by selective real-time polymerase chain reaction (SPCR), which can detect M184I/V mutants down to 0.2% of the viral population.Results SPCR revealed differences at amino acid position 184 in the plasma/CSF populations in 12 paired samples from eight patients. One plasma sample was positive by SPCR where direct sequencing showed wild-type M184. The other 11 paired samples showed quantitative differences in the mixed populations of the mutant or wild-type M184 quasispecies. Differences in other resistanceassociated mutations between plasma and CSF viruses were also found by direct sequencing. ConclusionsIn multi-treatment-experienced patients with therapy failure, differences in drug resistance patterns were found frequently between plasma and CSF in both minor and major viral populations. To what extent this was a true biological phenomenon remains to be established, and the clinical relevance of these findings is yet to be determined.

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Section: Discussionsupporting

confidence: 86%

Difference in drug resistance patterns between minor HIV‐1 populations in cerebrospinal fluid and plasma

et al. 2009

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“…Y115 (green) appears to play a key role as a gate, discriminating dNTPs from rNTPs (Boyer et al, 2000; Gao et al, 1997; Joyce, 1997; Martín-Hernández, Domingo, and Menéndez-Arias, 1996). Mutations at residue M184 (purple), which naturally contributes to mismatch selectivity, are frequently found in HIV-1 drug resistant patients (Menéndez-Arias, 2008; Pandey et al, 1996; Ray, Basavapathruni, and Anderson, 2002; Svedhem et al, 2007; Yang et al, 2008; Yoshimura et al, 1999). M184I, for example, is a transient 3TC resistant mutation, ultimately resulting in M184V (Frost et al, 2000; Mulder, Harari, and Simon, 2008; Svedhem et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…Mutations at residue M184 (purple), which naturally contributes to mismatch selectivity, are frequently found in HIV-1 drug resistant patients (Menéndez-Arias, 2008; Pandey et al, 1996; Ray, Basavapathruni, and Anderson, 2002; Svedhem et al, 2007; Yang et al, 2008; Yoshimura et al, 1999). M184I, for example, is a transient 3TC resistant mutation, ultimately resulting in M184V (Frost et al, 2000; Mulder, Harari, and Simon, 2008; Svedhem et al, 2007). It was found that the beta branched side chain of isoleucine sterically blocks the entry of 3TC into the active site of RT (Sarafianos et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

The impact of molecular manipulation in residue 114 of human immunodeficiency virus type-1 reverse transcriptase on dNTP substrate binding and viral replication

et al. 2012

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Human immunodeficiency virus type-1 (HIV-1) reverse transcriptase (RT) has a unique tight binding to dNTP substrates. Structural modeling of Ala-114 of HIV-1 RT suggests that longer side chains at this residue can reduce the space normally occupied by the sugar moiety of an incoming dNTP. Indeed, mutations at Ala-114 decrease the ability of RT to synthesize DNA at low dNTP concentrations and reduce the dNTP-binding affinity (Kd) of RT. However, the Kd values of WT and A114C RT remained equivalent with an acylic dNTP substrate. Finally, mutant A114 RT HIV-1 vectors displayed a greatly reduced transduction in nondividing human lung fibroblasts (HLFs), while WT HIV-1 vector efficiently transduced both dividing and nondividing HLFs. Together these data support that the A114 residue of HIV-1 RT plays a key mechanistic role in the dNTP binding of HIV-1 RT and the unique viral infectivity of target cell types with low dNTP pools.

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“…However, it is still not clear to which extent infection of new cells occurs during the phase of viral decay after initiation of suppressive ART, and whether viral replication can lead to the early selection of drugresistant viruses. When treatment failure occurs after a period of undetectable viremia, minority drug-resistant quasispecies can emerge as the major viral population [Metzner et al, 2003;Charpentier et al, 2004;Roquebert et al, 2006;Svedhem et al, 2007]. These variants can either be pre-existing or evolve in the setting of incomplete viral suppression.…”

Section: Introductionmentioning

confidence: 99%

Selection of drug‐resistant HIV‐1 during the early phase of viral decay is uncommon in treatment‐naïve patients initiated on a three‐ or four‐drug antiretroviral regimen including lamivudine

Bergroth¹,

Ekici²,

Gisslén³

et al. 2008

Journal of Medical Virology

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Therapy failure due to drug resistance development is a common phenomenon in HIV-infected patients. However, when the drug pressure leads to the earliest selection of drug-resistant HIV-1 populations is still unclear. In this study, the extent to which selection of the HIV-1 reverse transcriptase M184I/V mutations occur during the initial phase of viral decay in treatment-naïve HIV-1 infected patients receiving antiretroviral therapy (ART) was examined. Plasma virus from three cohorts of treatment-naïve patients initiating quadruple (n ¼ 43), triple (n ¼ 14) or dual (n ¼ 15) lamivudine-containing ART were analyzed for M184I/V during the first 6 months of therapy using direct sequencing and a sensitive selective real-time PCR method. Among quadruple ART patients, who all were treated at primary HIV-1 infection, only one patient developed M184V after 6 weeks of therapy, having had wild-type virus at baseline. No mutations were found in chronically infected patients on triple ART. In patients on dual therapy, M184I/V mutants were found frequently. Selection of M184I/V mutants was found to be rare during the initial phase of viral decay after initiation of ART in adherent patients given a three or fourdrug combination, in contrast to those receiving a less potent regimen. The results suggest that triple and quadruple lamivudine þ PI or PI/r containing ART given to treatment-naïve adherent patients is potent enough to prevent development of resistance during the first months of therapy.

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Presence of M184I/V in minor HIV‐1 populations of patients with lamivudine and/or didanosine treatment failure

Cited by 5 publications

References 21 publications

Difference in drug resistance patterns between minor HIV‐1 populations in cerebrospinal fluid and plasma

Difference in drug resistance patterns between minor HIV‐1 populations in cerebrospinal fluid and plasma

The impact of molecular manipulation in residue 114 of human immunodeficiency virus type-1 reverse transcriptase on dNTP substrate binding and viral replication

Selection of drug‐resistant HIV‐1 during the early phase of viral decay is uncommon in treatment‐naïve patients initiated on a three‐ or four‐drug antiretroviral regimen including lamivudine

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