The same mutation that encodes low-level human immunodeficiency virus type 1 resistance to 2',3'-dideoxyinosine and 2',3'-dideoxycytidine confers high-level resistance to the (-) enantiomer of 2',3'-dideoxy-3'-thiacytidine

Gao, Qing; Gu, Zhengxian; Parniak, Michael A.; Js, Cameron; Cammack, N.; Boucher, Charles A.; Wainberg, Mark A.

doi:10.1128/aac.37.6.1390

Cited by 231 publications

(205 citation statements)

References 17 publications

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“…Consistent with previous studies, we also observed that the M184I Clone 7 RT variant showed a higher fidelity compared with Met-184 clone 3 RT. 4 Finally, we attempted to elucidate how the M184I mutation restricts the dNTP binding of HIV-1 RT by comparing the active site structures of the binary complex form (RT⅐T⅐P) of wild-type and M184I HIV-1 RTs, which were previously solved. Previous structural analysis suggested that the two ␤-branch amino acid mutations (Val and Ile) at position 184 of HIV-1 RT introduce more rigid side chains to the active site, compared with the wild-type Met residue.…”

Section: Discussionmentioning

confidence: 99%

“…One initial explanation for the delayed selection of the M184V mutation is the requirement of two nucleotide mutations to develop the final M184V mutation from the wild-type methionine codon (ATG). In contrast, the M184I mutation requires only a single nucleotide mutation from the Met codon, which may result in its early selection during 3TC therapy (3)(4)(5)(6)(7).…”

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confidence: 99%

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Reduced dNTP Binding Affinity of 3TC-resistant M184I HIV-1 Reverse Transcriptase Variants Responsible for Viral Infection Failure in Macrophage

Jamburuthugoda

Santos-Velazquez

Skasko

et al. 2008

Journal of Biological Chemistry

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We characterized HIV-1 reverse transcriptase (RT) variants either with or without the (؊)-2,3-deoxy-3-thiacytidine-resistant M184I mutation isolated from a single HIV-1 infected patient. First, unlike variants with wild-type M184, M184I RT variants displayed significantly reduced DNA polymerase activity at low dNTP concentrations, which is indicative of reduced dNTP binding affinity. Second, the M184I variant displayed a ϳ10-to 13-fold reduction in dNTP binding affinity, compared with the Met-184 variant. However, the k pol values of these two RTs were similar. Third, unlike HIV-1 vectors with wild-type RT, the HIV-1 vector harboring M184I RT failed to transduce cell types containing low dNTP concentrations, such as human macrophage, likely due to the reduced DNA polymerization activity of the M184I RT under low cellular dNTP concentration conditions. Finally, we compared the binary complex structures of wild-type and M184I RTs. The Ile mutation at position 184 with a longer and more rigid ␤-branched side chain, which was previously known to alter the RT-template interaction, also appears to deform the shape of the dNTP binding pocket. This can restrict ground state dNTP binding and lead to inefficient DNA synthesis particularly at low dNTP concentrations, ultimately contributing to viral replication failure in macrophage and instability in vivo of the M184I mutation.(Ϫ)-2Ј,3Ј-Deoxy-3Ј-thiacytidine (3TC), 3 a deoxycytidine analog reverse transcriptase (RT) inhibitor, has been routinely included in the anti-HIV-1 drug regime (1, 2). During 3TC therapy, two amino acid substitutions at position 184 of RT are sequentially selected, conferring viral resistance to this drug. The M184I mutation is detected earlier, and eventually replaced with the M184V mutation. One initial explanation for the delayed selection of the M184V mutation is the requirement of two nucleotide mutations to develop the final M184V mutation from the wild-type methionine codon (ATG). In contrast, the M184I mutation requires only a single nucleotide mutation from the Met codon, which may result in its early selection during 3TC therapy (3-7).Structural analysis later provided a functional explanation for the instability in vivo of the M184I mutation. The M184I mutation alters the RT interaction with the template nucleotide more significantly than the M184V mutation, leading to more severely decreased processivity, compared with the M184V RT (8). Indeed, the distributive DNA synthesis catalyzed by the M184I RT has been a major explanation for the instability in vivo of this mutation and its rapid transition to the M184V mutation. The long ␤-branched side chains of these two mutations efficiently block the entry of 3TCTP to the active site (8, 9). Interestingly, pre-steady-state kinetic studies of the M184V mutant demonstrated that the M184V mutation only slightly (1-to 2-fold) affects K d (dNTP binding affinity), but not k pol (conformational change/chemical catalysis) steps of HIV-1 RT with normal dNTP substrates, implying that the Val mutation d...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Reduced dNTP Binding Affinity of 3TC-resistant M184I HIV-1 Reverse Transcriptase Variants Responsible for Viral Infection Failure in Macrophage

Jamburuthugoda

Santos-Velazquez

Skasko

et al. 2008

Journal of Biological Chemistry

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“…At 2, 4 and 6 months after initiation of entecavir, 12%, 61% and 96% of the clones, respectively, harbored the M184V mutation ( Figure 3B). This mutation confers high level resistance to the anti-HIV drugs lamivudine and emtricitabine (16)(17)(18). No other known resistance mutations were observed.…”

Section: The M184v Mutant Virus Is Selected By and Is Resistant To Enmentioning

confidence: 99%

The HBV Drug Entecavir — Effects on HIV-1 Replication and Resistance

et al. 2007

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“…Mutations in the YMDD motif of the HBV polymerase gene, potentially associated with diminished response to lamivudine, [6][7][8][9] were detected as described. 5,10 During the course of the study, we used an operational definition of virological breakthrough (HBV DNA Ͼ10 pg/mL on 2 successive determinations, after at least 2 previous values had been undetectable) to identify patients for whom YMDD-mutant HBV evaluation would be appropriate.…”

Section: Methodsmentioning

confidence: 99%

Extended lamivudine retreatment for chronic hepatitis B: Maintenance of viral suppression after discontinuation of therapy

Dienstag¹,

Schiff²,

Mitchell³

et al. 1999

Hepatology

188

128

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In patients with chronic hepatitis B, brief lamivudine therapy suppresses hepatitis B virus (HBV) DNA but results infrequently in sustained losses of virus replication posttreatment. We evaluated treatment response and its posttreatment durability during up to 18 months of lamivudine therapy (100 mg/d) in 24 patients who had hepatitis B e antigen (HBeAg) despite 1 to 3 months of prior therapy. Therapy was to be stopped after HBeAg loss or seroconversion (acquisition of antibody to HBeAg); posttreatment monitoring continued for 6 months. During therapy, which was well tolerated, HBV DNA became undetectable in all evaluable patients, accompanied by reduced alanine transaminase (ALT) activity. The cumulative 18-month confirmed loss of HBeAg during therapy was 9 of 24 (38%) and seroconversion was 5 of 24 (21%). Therapy was discontinued after HBeAg loss/seroconversion in 7 patients, and Chronic hepatitis B virus (HBV) infection occurs in approximately 5% of the world' s population and is among the top 10 causes of death. Although interferon alfa has been approved as therapy for chronic hepatitis B, such treatment is suboptimal, yielding clinical benefit in a minority of patients. Lamivudine is an oral dideoxynucleoside that inhibits reverse transcription by causing chain termination of nascent viral DNA in human immunodeficiency virus (HIV) and HBV infection. 1 As reported previously, phase-II dose-ranging trials in North American and western European patients with chronic hepatitis B included daily doses of 5 to 600 mg administered for 1 to 6 months. 2-4 Therapy was well tolerated, doses of 100 mg or more suppressed serum HBV DNA levels consistently during therapy, and no significant advantage was identified for doses above 100 mg. 3,4 A sustained response posttreatment, however, defined as the loss of hepatitis B e antigen (HBeAg) and failure of HBV DNA to reappear after discontinuation of therapy, occurred in only 4% to 12% of patients in these dose-ranging studies. In a recently completed placebo-controlled phase-III trial involving 358 Chinese patients, Lai et al. 5 reported that 12 months of lamivudine therapy at a dose of 100 mg/d was associated with histological improvement in 67% of patients and HBeAg seroconversion in 16%, which is significantly better than response rates observed in concurrent placebo controls. This study in Asian patients, however, did not address treatmentstopping criteria; regardless of HBeAg status at the end of 12 months of therapy, all patients were enrolled in a continuingtreatment follow-up study. 5 In the present study, we wished to determine whether prolonged lamivudine therapy in Western patients would be safe and tolerable and result in loss of HBeAg and HBeAg seroconversion in a higher proportion of patients compared with the shorter dosing regimens studied previously. We also sought to determine whether lamivudine therapy could be withdrawn after HBeAg loss or HBeAg seroconversion. Therefore, we undertook an extended-treatment trial in previously Abbreviations: HBV, hepatitis...

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The same mutation that encodes low-level human immunodeficiency virus type 1 resistance to 2',3'-dideoxyinosine and 2',3'-dideoxycytidine confers high-level resistance to the (-) enantiomer of 2',3'-dideoxy-3'-thiacytidine

Cited by 231 publications

References 17 publications

Reduced dNTP Binding Affinity of 3TC-resistant M184I HIV-1 Reverse Transcriptase Variants Responsible for Viral Infection Failure in Macrophage

Reduced dNTP Binding Affinity of 3TC-resistant M184I HIV-1 Reverse Transcriptase Variants Responsible for Viral Infection Failure in Macrophage

The HBV Drug Entecavir — Effects on HIV-1 Replication and Resistance

Extended lamivudine retreatment for chronic hepatitis B: Maintenance of viral suppression after discontinuation of therapy

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