An integrated molecular dynamics, principal component analysis and residue interaction network approach reveals the impact of M184V mutation on HIV reverse transcriptase resistance to lamivudine

2014 ◽  
Vol 10 (8) ◽  
pp. 2215-2228 ◽  
Author(s):  
Soumendranath Bhakat ◽  
Alberto J. M. Martin ◽  
Mahmoud E. S. Soliman
Keyword(s):  
Reverse Transcriptase ◽  
Interaction Network ◽  
Principal Component ◽  
Hiv Reverse Transcriptase ◽  
Residue Interaction ◽  
Resistant Strains ◽  
Hiv Rt ◽  
Drug Resistant Strains ◽  
The Impact ◽  
M184v Mutation

The emergence of different drug resistant strains of HIV-1 reverse transcriptase (HIV RT) remains of prime interest in relation to viral pathogenesis as well as drug development.

scholarly journals Effects of the W153L Substitution in HIV Reverse Transcriptase on Viral Replication and Drug Resistance to Multiple Categories of Reverse Transcriptase Inhibitors

2014 ◽  
Vol 58 (8) ◽  
pp. 4515-4526 ◽  
Author(s):  
Hong-Tao Xu ◽  
Susan P. Colby-Germinario ◽  
Maureen Oliveira ◽  
Daniel Rajotte ◽  
Richard Bethell ◽  
...  
Keyword(s):  
Viral Replication ◽  
Reverse Transcriptase ◽  
Rnase H ◽  
Hiv Reverse Transcriptase ◽  
Compound A ◽  
Enzymatic Function ◽  
Biochemical Assays ◽  
Rt Inhibitors ◽  
The Impact ◽  
Hiv 1

ABSTRACTA W153L substitution in HIV-1 reverse transcriptase (RT) was recently identified by selection with a novel nucleotide-competing RT inhibitor (NcRTI) termed compound A that is a member of the benzo[4,5]furo[3,2,d]pyrimidin-2-one NcRTI family of drugs. To investigate the impact of W153L, alone or in combination with the clinically relevant RT resistance substitutions K65R (change of Lys to Arg at position 65), M184I, K101E, K103N, E138K, and Y181C, on HIV-1 phenotypic susceptibility, viral replication, and RT enzymatic function, we generated recombinant RT enzymes and viruses containing each of these substitutions or various combinations of them. We found that W153L-containing viruses were impaired in viral replicative capacity and were hypersusceptible to tenofovir (TFV) while retaining susceptibility to most nonnucleoside RT inhibitors. The nucleoside 3TC retained potency against W153L-containing viruses but not when the M184I substitution was also present. W153L was also able to reverse the effects of the K65R substitution on resistance to TFV, and K65R conferred hypersusceptibility to compound A. Biochemical assays demonstrated that W153L alone or in combination with K65R, M184I, K101E, K103N, E138K, and Y181C impaired enzyme processivity and polymerization efficiency but did not diminish RNase H activity, providing mechanistic insights into the low replicative fitness associated with these substitutions. We show that the mechanism of the TFV hypersusceptibility conferred by W153L is mainly due to increased efficiency of TFV-diphosphate incorporation. These results demonstrate that compound A and/or derivatives thereof have the potential to be important antiretroviral agents that may be combined with tenofovir to achieve synergistic results.

Evaluation of 4-thiazolidinone derivatives as potential reverse transcriptase inhibitors against HIV-1 drug resistant strains

2017 ◽  
Vol 71 ◽  
pp. 211-218 ◽  
Author(s):  
Rahul Suryawanshi ◽  
Sushama Jadhav ◽  
Nandini Makwana ◽  
Dipen Desai ◽  
Devidas Chaturbhuj ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Drug Resistant ◽  
Reverse Transcriptase Inhibitors ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Hiv 1

scholarly journals 3′-Azido-3′-deoxythymidine drug resistance mutations in HIV-1 reverse transcriptase can induce long range conformational changes

1998 ◽  
Vol 95 (16) ◽  
pp. 9518-9523 ◽  
Author(s):  
Jingshan Ren ◽  
Robert M. Esnouf ◽  
Andrew L. Hopkins ◽  
E. Yvonne Jones ◽  
Ian Kirby ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Long Range ◽  
Conformational Changes ◽  
Active Site ◽  
Common Mechanism ◽  
Resistance Mutations ◽  
Hiv Reverse Transcriptase ◽  
Drug Resistance Mutations ◽  
Hiv Rt

HIV reverse transcriptase (RT) is one of the main targets for the action of anti-AIDS drugs. Many of these drugs [e.g., 3′-azido-3′-deoxythymidine (AZT) and 2′,3′-dideoxyinosine (ddI)] are analogues of the nucleoside substrates used by the HIV RT. One of the main problems in anti-HIV therapy is the selection of a mutant virus with reduced drug sensitivity. Drug resistance in HIV is generated for nucleoside analogue inhibitors by mutations in HIV RT. However, most of these mutations are situated some distance from the polymerase active site, giving rise to questions concerning the mechanism of resistance. To understand the possible structural bases for this, the crystal structures of AZT- and ddI-resistant RTs have been determined. For the ddI-resistant RT with a mutation at residue 74, no significant conformational changes were observed for the p66 subunit. In contrast, for the AZT-resistant RT (RTMC) bearing four mutations, two of these (at 215 and 219) give rise to a conformational change that propagates to the active site aspartate residues. Thus, these drug resistance mutations produce an effect at the RT polymerase site mediated simply by the protein. It is likely that such long-range effects could represent a common mechanism for generating drug resistance in other systems.

scholarly journals Host population structure and treatment frequency maintain balancing selection on drug resistance

2017 ◽  
Author(s):  
Sarah Cobey ◽  
Edward B. Baskerville ◽  
Caroline Colijn ◽  
William Hanage ◽  
Christophe Fraser ◽  
...  
Keyword(s):  
Population Structure ◽  
Balancing Selection ◽  
Antibiotic Use ◽  
Host Population ◽  
Antimicrobial Drugs ◽  
Treatment Frequency ◽  
Specific Variation ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
The Impact

AbstractIt is a truism that antimicrobial drugs select for resistance, but explaining pathogen- and population-specific variation in patterns of resistance remains an open problem. Like other common commensals, Streptococcus pneumoniae has demonstrated persistent coexistence of drug-sensitive and drug-resistant strains. Theoretically, this outcome is unlikely. We modeled the dynamics of competing strains of S. pneumoniae to investigate the impact of transmission dynamics and treatment-induced selective pressures on the probability of stable coexistence. We find that the outcome of competition is extremely sensitive to structure in the host population, although coexistence can arise from age-assortative transmission models with age-varying rates of antibiotic use. Moreover, we find that the selective pressure from antibiotics arises not so much from the rate of antibiotic use per se but from the frequency of treatment: frequent antibiotic therapy disproportionately impacts the fitness of sensitive strains. This same phenomenon explains why serotypes with longer durations of carriage tend to be more resistant. These dynamics may apply to other potentially pathogenic, microbial commensals and highlight how population structure, which is often omitted from models, can have a large impact.

scholarly journals Antimycobacterial and HIV-1 Reverse Transcriptase Activity of Julianaceae and Clusiaceae Plant Species from Mexico

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Rocio Gómez-Cansino ◽  
Clara Inés Espitia-Pinzón ◽  
María Guadalupe Campos-Lara ◽  
Silvia Laura Guzmán-Gutiérrez ◽  
Erika Segura-Salinas ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Antimycobacterial Activity ◽  
Reverse Transcriptase Activity ◽  
Hiv Reverse Transcriptase ◽  
Leaf Extracts ◽  
Calophyllum Brasiliense ◽  
Hplc Profiles ◽  
Low Toxicity ◽  
Hiv Rt

The extracts of 14 Julianaceae and 5 Clusiaceae species growing in Mexico were testedin vitro(50 µg/mL) againstMycobacterium tuberculosisH37Rv and HIV reverse transcriptase (HIV-RT). The Julianaceae bark and leaf extracts inhibitedM. tuberculosis(>84.67%) and HIV-RT (<49.89%). The Clusiaceae leaves extracts also inhibited both targets (>58.3% and >67.6%), respectively. The IC50values for six selected extracts and their cytotoxicity (50 µg/mL) to human macrophages were then determined.Amphipterygium glaucum,A. molle, andA. simplicifoliumfairly inhibitedM. tuberculosiswith IC50of 1.87–2.35 µg/mL; but their IC50against HIV-RT was 59.25–97.83 µg/mL.Calophyllum brasiliense,Vismia baccifera, andVismia mexicanaeffect onM. tuberculosiswas noteworthy (IC503.02–3.64 µg/mL) and also inhibited RT-HIV (IC5026.24–35.17 µg/mL). These 6 extracts (50 µg/mL) presented low toxicity to macrophages (<23.8%). The HPLC profiles ofA. glaucum,A. molle, andA. simplicifoliumindicated that their antimycobacterial activity cannot be related to masticadienonic, 3α, or 3β-hydromasticadienonic acids, suggesting that other compounds may be responsible for the observed activity or this might be a synergy result. The anti-HIV-RT and antimycobacterial activities induced byC. brasiliensecan be attributed to the content of calanolides A, B, as well as soulatrolide.

scholarly journals Quantification of the Effects on Viral DNA Synthesis of Reverse Transcriptase Mutations Conferring Human Immunodeficiency Virus Type 1 Resistance to Nucleoside Analogues

2005 ◽  
Vol 79 (2) ◽  
pp. 812-822 ◽  
Author(s):  
Francine Bouchonnet ◽  
Elisabeth Dam ◽  
Fabrizio Mammano ◽  
Vaea de Soultrait ◽  
Gaëlle Henneré ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Dna Synthesis ◽  
Nucleoside Analogues ◽  
Resistance Mutations ◽  
Viral Dna ◽  
Immunodeficiency Virus ◽  
The Impact ◽  
Hiv 1 ◽  
M184v Mutation

ABSTRACT Human immunodeficiency virus type I (HIV-1) reverse transcriptase (RT) resistance mutations reduce the susceptibility of the virus to nucleoside analogues but may also impair viral DNA synthesis. To further characterize the effect of nucleoside analogue resistance mutations on the efficiency and kinetics of HIV-1 DNA synthesis and to evaluate the impact of the depletion of deoxynucleoside triphosphates (dNTP) on this process, DNA synthesis was evaluated by allowing DNA synthesis to proceed with natural HIV-1 templates and primers, either within permeabilized viral particles or in newly infected cells, and quantifying the products by real-time PCR. Three recombinant viruses derived from three pNL4-3 molecular clones expressing mutations associated with resistance to zidovudine: a clone expressing RT mutation M184V, a clone expressing mutations M41L plus T215Y (M41L+T215Y), and clinical isolate BV34 (carrying seven resistance mutations). Following infection of P4 cells, the BV34 mutant, but not viruses expressing the M184V mutation or M41L+T215Y, exhibited a defect in DNA synthesis. Importantly, however, for mutants carrying the M184V mutation or M41L+T215Y mutations, a defect could be detected by using target cells in which dATP pools had been reduced by pretreatment with hydroxyurea. Based on these observations, we developed a recombinant-virus assay to assess the effects of hydroxyurea pretreatment on infectivity of viruses carrying plasma-derived RT sequences from patients with nucleoside resistance. Using this assay, we found that many, but not all, viruses carrying RT resistance mutations display an increased sensitivity to hydroxyurea, suggesting that the impact of RT resistance mutations on viral replication may be more profound in cell populations characterized by smaller dNTP pools.

PASS-based approach to predict HIV-1 reverse transcriptase resistance

2017 ◽  
Vol 15 (02) ◽  
pp. 1650040 ◽  
Author(s):  
Olga Tarasova ◽  
Dmitry Filimonov ◽  
Vladimir Poroikov
Keyword(s):  
Amino Acid ◽  
Reverse Transcriptase ◽  
Open Data ◽  
Amino Acid Substitutions ◽  
Hiv Reverse Transcriptase ◽  
Hiv Rt ◽  
Hiv Drugs ◽  
Rt Inhibitors ◽  
Anti Hiv ◽  
Hiv 1

HIV reverse transcriptase (RT) inhibitors targeting the early stages of virus–host interactions are of great interest to scientists. Acquired HIV RT resistance happens due to mutations in a particular region of the pol gene encoding the HIV RT amino acid sequence. We propose an application of the previously developed PASS algorithm for prediction of amino acid substitutions potentially involved in the resistance of HIV-1 based on open data. In our work, we used more than 3200 HIV-1 RT variants from the publicly available Stanford HIV RT and protease sequence database already tested for 10 anti-HIV drugs including both nucleoside and non-nucleoside RT inhibitors. We used a particular amino acid residue and its position to describe primary structure-resistance relationships. The average balanced accuracy of the prediction obtained in 20-fold cross-validation for the Phenosense dataset was about 88% and for the Antivirogram dataset was about 79%. Thus, the PASS-based algorithm may be used for prediction of the amino acid substitutions associated with the resistance of HIV-1 based on open data. The computational approach for the prediction of HIV-1 associated resistance can be useful for the selection of RT inhibitors for the treatment of HIV infected patients in the clinical practice. Prediction of the HIV-1 RT associated resistance can be useful for the development of new anti-HIV drugs active against the resistant variants of RT. Therefore, we propose that this study can be potentially useful for anti-HIV drug development.

scholarly journals Entecavir Therapy Induces de Novo HIV Reverse‐Transcriptase M184V Mutation in an Antiretroviral Therapy–Naive Patient

2008 ◽  
Vol 46 (9) ◽  
pp. e88-e91 ◽  
Author(s):  
Martin R. Jakobsen ◽  
Hanne Arildsen ◽  
Henrik B. Krarup ◽  
Martin Tolstrup ◽  
Lars Østergaard ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Reverse Transcriptase ◽  
De Novo ◽  
Hiv Reverse Transcriptase ◽  
Naive Patient ◽  
M184v Mutation
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