title: HIV-1 resistance profile of the novel nucleoside reverse transcriptase inhibitor beta-D-2',3'-dideoxy-2',3'-didehydro-5-fluorocytidine (Reverset).
abstract: Nucleoside reverse transcriptase inhibitors (NRTIs) represent the cornerstone of highly active antiretroviral therapy when combined with non-nucleoside reverse transcriptase inhibitors (NNRTIs) or HIV-1 protease inhibitors (PIs). Unlike the NNRTIs and PIs, NRTIs must be successively phosphorylated by cellular kinases to a triphosphate form, which represents the active metabolite possessing antiviral activity. Emergence of viral resistance to NRTIs has severely hampered treatment options for persons infected with HIV-1. As such, there is an urgent need to develop NRTIs capable of suppressing NRTI-resistant strains of HIV-1. We have recently reported that the cytidine analogue D-d4FC (DPC817, Reverset) effectively inhibits clinically prevalent resistant strains of HIV-1. In this report, we have extended these findings and now describe a detailed resistance profile for this novel NRTI. By examining a panel of 50 viruses carrying RTs derived from HIV-1 clinical isolates displaying a wide range of NRTI resistance mutations, we report that the median fold increase in effective antiviral concentration for such a panel of viruses is 3.2, which is comparable to tenofovir (2.8-fold) and didanosine (2.4-fold). D-d4FC is highly effective at inhibiting subsets of lamivudine- and zidovudine-resistant variants but, like other NRTIs, seems less potent against multi-NRTI-resistant viruses, particularly those carrying the Q151M complex of mutations. Finally, in vitro selections for HIV-1 mutants capable of replicating in the presence of D-d4FC yielded a mutant carrying the RT K65R mutation. This mutation confers 5.3- to 8.7-fold resistance to D-d4FC in vitro. These findings suggest that D-d4FC may represent an alternative NRTI for the treatment of individuals infected with lamivudine- and zidovudine-resistant strains of HIV-1.
authors.affiliation: Department of Virology, The DuPont Pharmaceuticals Company (Bristol-Myers Squibb Pharmaceuticals Company), Del., USA.
authors.forename: Romas
authors.initials: R
authors.lastname: Geleziunas
authors.forename: Karen
authors.initials: K
authors.lastname: Gallagher
authors.forename: Hangchun
authors.initials: H
authors.lastname: Zhang
authors.forename: Lee
authors.initials: L
authors.lastname: Bacheler
authors.forename: Sena
authors.initials: S
authors.lastname: Garber
authors.forename: Jing-Tao
authors.initials: JT
authors.lastname: Wu
authors.forename: Guoen
authors.initials: G
authors.lastname: Shi
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Otto
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
authors.forename: Susan
authors.initials: S
authors.lastname: Erickson-Viitanen
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D003570:Cytidine Triphosphate / Q000031:analogs & derivatives / Q000032:analysis / Q000494:pharmacology*; D016049:Didanosine / Q000494:pharmacology; D024921:Drug Resistance, Multiple, Viral / Q000235:genetics; D005838:Genotype; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology; D009154:Mutation; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D013045:Species Specificity; D000068698:Tenofovir; D014162:Transfection; D016047:Zalcitabine / Q000031:analogs & derivatives; D015215:Zidovudine / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine; D003570:Cytidine Triphosphate; D016047:Zalcitabine; D000068698:Tenofovir; D054303:HIV Reverse Transcriptase; D000225:Adenine; D016049:Didanosine; C099405:dexelvucitabine