Dataset Information

Understanding the molecular mechanism of sequence dependent tenofovir removal by HIV-1 reverse transcriptase: differences in primer binding site versus polypurine tract.

ABSTRACT: Tenofovir (TFV) is a nucleotide reverse transcriptase inhibitor (NtRTI) that is often administered as first-line therapy against human immunodeficiency virus type-1 (HIV-1) infection and acts as a chain terminator when incorporated into viral DNA. However, HIV-1 reverse transcriptase (RT) excises TFV in the presence of either ATP or pyrophosphate, which is an important drug resistance mechanism that would interfere with the effective treatment. Previous studies have shown conflicting results on excision efficiencies for TFV-terminated primer-templates derived from either primer binding site (PBS) or polypurine tract (PPT) sequences. To provide mechanistic insight into the variation in TFV removal from both sequences that are vital for the HIV-1 life cycle, we compared the efficiencies of removal reaction in response to sequence dependence via utilizing blocked PBS and PPT primer-templates. We found an enhanced TFV excision with PPT sequence over PBS sequence through ATP-mediated removal and a subsequent incorporation of ATP into the unblocked primers. Furthermore, the rate of pyrophosphorolytic excision of TFV from PPT sequence was 21-fold higher than that for the PBS sequence. However, the addition of efavirenz, nonnucleoside reverse transcriptase inhibitor (NNRTI), to the removal reaction effectively inhibits the TFV excision from both primers by forming a stable complex that would leave TFV inaccessible for excision. These results illuminate the degree of primer-template sequence contribution on TFV removal as well as increase our understanding of the molecular mechanism for the beneficial effects of widely used combinations of antiretroviral regimens in the context of synergistic antiviral activity and drug resistance.

SUBMITTER: Iyidogan P

PROVIDER: S-EPMC3398203 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Understanding the molecular mechanism of sequence dependent tenofovir removal by HIV-1 reverse transcriptase: differences in primer binding site versus polypurine tract.

Iyidogan Pinar P Anderson Karen S KS

Antiviral research 20120601 2

Tenofovir (TFV) is a nucleotide reverse transcriptase inhibitor (NtRTI) that is often administered as first-line therapy against human immunodeficiency virus type-1 (HIV-1) infection and acts as a chain terminator when incorporated into viral DNA. However, HIV-1 reverse transcriptase (RT) excises TFV in the presence of either ATP or pyrophosphate, which is an important drug resistance mechanism that would interfere with the effective treatment. Previous studies have shown conflicting results on ...[more]

PMID: 22664235

Similar Datasets

Project description:Antiviral pre-exposure prophylaxis (PrEP) through daily drug administration can protect healthy individuals from HIV-1 infection. While PrEP was recently approved by the FDA, the potential long-term consequences of PrEP implementation remain entirely unclear. The aim of this study is to predict the efficacy of different prophylactic strategies with the pro-drug tenofovir-disoproxil-fumarate (TDF) and to assess the sensitivity towards timing- and mode of TDF administration (daily- vs. single dose), adherence and the number of transmitted viruses. We developed a pharmacokinetic model for TDF and its active anabolite tenofovir-diphosphate (TFV-DP) and validated it with data from 4 different trials, including 4 distinct dosing regimes. Pharmacokinetics were coupled to an HIV model and viral decay following TDF mono-therapy was predicted, consistent with available data. Subsequently, a stochastic approach was used to estimate the % infections prevented by (i) daily TDF-based PrEP, (ii) one week TDF started either shortly before, or -after viral exposure and (iii) a single dose oral TDF before viral challenge (sd-PrEP). Analytical solutions were derived to assess the relation between intracellular TFV-DP concentrations and prophylactic efficacy. The predicted efficacy of TDF was limited by a slow accumulation of active compound (TFV-DP) and variable TFV-DP half-life and decreased with increasing numbers of transmitted viruses. Once daily TDF-based PrEP yielded [Formula: see text]80% protection, if at least 40% of pills were taken. Sd-PrEP with 300 mg or 600 mg TDF could prevent [Formula: see text]50% infections, when given at least before virus exposure. The efficacy dropped to [Formula: see text]10%, when given 1 h before 24 h exposure. Efficacy could not be increased with increasing dosage or prolonged administration. Post-exposure prophylaxis poorly prevented infection. The use of drugs that accumulate more rapidly, or local application of tenofovir gel may overcome the need for drug administration long before virus exposure.

Dataset Information

Understanding the molecular mechanism of sequence dependent tenofovir removal by HIV-1 reverse transcriptase: differences in primer binding site versus polypurine tract.

Publications

Understanding the molecular mechanism of sequence dependent tenofovir removal by HIV-1 reverse transcriptase: differences in primer binding site versus polypurine tract.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets