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NNRTI-selected mutations at codon 190 of human immunodeficiency virus type 1 reverse transcriptase decrease susceptibility to stavudine and zidovudine. 2007

Stefania Paolucci, and Fausto Baldanti, and Giulia Campanini, and Reynel Cancio, and Amalia Belfiore, and Giovanni Maga, and Giuseppe Gerna
Servizio di Virologia, IRCCS Policlinico San Matteo, 27100 Pavia, Italy.

The non-nucleoside reverse transcriptase (RT) inhibitor (NNRTI)-binding pocket of HIV-1 RT spans codons 100-110, 180-190 and 220-240 and mutations in these domains are responsible for HIV-1 NNRTI resistance. Recombinant HIV-1 strains carrying G190S/A/E, G190S+T215Y, T215Y and K103N mutations were constructed to evaluate susceptibility to both NNRTIs and nucleoside RT inhibitors (NRTIs). In addition, purified recombinant RT enzymes were obtained to determine the degree of in vitro inhibition by drugs of both classes. High-level resistance to nevirapine and moderate level resistance to both stavudine and zidovudine were associated with G190S/A/E substitutions. The simultaneous presence of G190S and T215Y decreased stavudine and zidovudine susceptibility more than T215Y alone. On the other hand, G190S was associated with a marked decrease in RT catalytic efficiency, while T215Y showed a more limited effect. Interestingly, the simultaneous presence of G190S and T215Y was associated with a reduction in the impairment of the G190S-mutated enzyme. Mutations in the HIV-1 RT NNRTI binding pocket may be associated with cross-resistance to NRTI. Selection of double mutants, with further decrease in NRTI susceptibility, might be favoured by the compensatory effect of T215Y on the reduction of RT catalytic efficiency associated with G190S.

UI MeSH Term Description Entries
D008826 Microbial Sensitivity Tests Any tests that demonstrate the relative efficacy of different chemotherapeutic agents against specific microorganisms (i.e., bacteria, fungi, viruses). Bacterial Sensitivity Tests,Drug Sensitivity Assay, Microbial,Minimum Inhibitory Concentration,Antibacterial Susceptibility Breakpoint Determination,Antibiogram,Antimicrobial Susceptibility Breakpoint Determination,Bacterial Sensitivity Test,Breakpoint Determination, Antibacterial Susceptibility,Breakpoint Determination, Antimicrobial Susceptibility,Fungal Drug Sensitivity Tests,Fungus Drug Sensitivity Tests,Sensitivity Test, Bacterial,Sensitivity Tests, Bacterial,Test, Bacterial Sensitivity,Tests, Bacterial Sensitivity,Viral Drug Sensitivity Tests,Virus Drug Sensitivity Tests,Antibiograms,Concentration, Minimum Inhibitory,Concentrations, Minimum Inhibitory,Inhibitory Concentration, Minimum,Inhibitory Concentrations, Minimum,Microbial Sensitivity Test,Minimum Inhibitory Concentrations,Sensitivity Test, Microbial,Sensitivity Tests, Microbial,Test, Microbial Sensitivity,Tests, Microbial Sensitivity
D009154 Mutation Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations. Mutations
D015215 Zidovudine A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by an azido group. This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains. The compound is a potent inhibitor of HIV replication, acting as a chain-terminator of viral DNA during reverse transcription. It improves immunologic function, partially reverses the HIV-induced neurological dysfunction, and improves certain other clinical abnormalities associated with AIDS. Its principal toxic effect is dose-dependent suppression of bone marrow, resulting in anemia and leukopenia. AZT (Antiviral),Azidothymidine,3'-Azido-2',3'-Dideoxythymidine,3'-Azido-3'-deoxythymidine,AZT Antiviral,AZT, Antiviral,BW A509U,BWA-509U,Retrovir,3' Azido 2',3' Dideoxythymidine,3' Azido 3' deoxythymidine,Antiviral AZT,BWA 509U,BWA509U
D015497 HIV-1 The type species of LENTIVIRUS and the etiologic agent of AIDS. It is characterized by its cytopathic effect and affinity for the T4-lymphocyte. Human immunodeficiency virus 1,HIV-I,Human Immunodeficiency Virus Type 1,Immunodeficiency Virus Type 1, Human
D054303 HIV Reverse Transcriptase A reverse transcriptase encoded by the POL GENE of HIV. It is a heterodimer of 66 kDa and 51 kDa subunits that are derived from a common precursor protein. The heterodimer also includes an RNAse H activity (RIBONUCLEASE H, HUMAN IMMUNODEFICIENCY VIRUS) that plays an essential role the viral replication process. Reverse Transcriptase, HIV,Reverse Transcriptase, Human Immunodeficiency Virus,Transcriptase, HIV Reverse
D018119 Stavudine A dideoxynucleoside analog that inhibits reverse transcriptase and has in vitro activity against HIV. 2',3'-Didehydro-3'-deoxythymidine,D4T,2',3'-Didehydro-2',3'-dideoxythmidine,BMY-27857,Stavudine, Monosodium Salt,Zerit,2',3' Didehydro 3' deoxythymidine,BMY 27857,BMY27857
D018894 Reverse Transcriptase Inhibitors Inhibitors of reverse transcriptase (RNA-DIRECTED DNA POLYMERASE), an enzyme that synthesizes DNA on an RNA template. Reverse Transcriptase Inhibitor,Inhibitors, Reverse Transcriptase,Inhibitor, Reverse Transcriptase,Transcriptase Inhibitor, Reverse
D019380 Anti-HIV Agents Agents used to treat AIDS and/or stop the spread of the HIV infection. These do not include drugs used to treat symptoms or opportunistic infections associated with AIDS. AIDS Drug,AIDS Drugs,Anti-AIDS Agents,Anti-AIDS Drug,Anti-HIV Agent,Anti-HIV Drug,Anti-AIDS Drugs,Anti-HIV Drugs,Agent, Anti-HIV,Agents, Anti-AIDS,Agents, Anti-HIV,Anti AIDS Agents,Anti AIDS Drug,Anti AIDS Drugs,Anti HIV Agent,Anti HIV Agents,Anti HIV Drug,Anti HIV Drugs,Drug, AIDS,Drug, Anti-AIDS,Drug, Anti-HIV,Drugs, AIDS,Drugs, Anti-AIDS,Drugs, Anti-HIV
D019829 Nevirapine A potent, non-nucleoside reverse transcriptase inhibitor used in combination with nucleoside analogues for treatment of HIV INFECTIONS and AIDS. BI-RG-587,Nevirapine Hemihydrate,Viramune,BI RG 587,BIRG587,Hemihydrate, Nevirapine
D019943 Amino Acid Substitution The naturally occurring or experimentally induced replacement of one or more AMINO ACIDS in a protein with another. If a functionally equivalent amino acid is substituted, the protein may retain wild-type activity. Substitution may also diminish, enhance, or eliminate protein function. Experimentally induced substitution is often used to study enzyme activities and binding site properties. Amino Acid Substitutions,Substitution, Amino Acid,Substitutions, Amino Acid

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