Anti-human immunodeficiency virus activities of the beta-L enantiomer of 2',3'-dideoxycytidine and its 5-fluoro derivative in vitro

Gosselin, Gilles; Schinazi, Raymond F.; Sommadossi, Jean Pierre; Mathé, Christophe; Bergogne, M.-C.; Aubertin, Anne-Marie; Kirn, A.; Imbach, Jean‐Louis

doi:10.1128/aac.38.6.1292

Cited by 131 publications

(62 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Animals in group B were treated with (Ϫ)-FTC (8 mg/kg given once daily beginning 1 day prior to virus inoculation) in order to prevent reversion of M184V (58). (Ϫ)-FTC is an analog of 3TC with stronger in vitro activity and an improved pharmacokinetic profile (12,13). Both groups became persistently infected and had similar viral RNA levels from 2 weeks after inoculation until 46 weeks when PMPA was started in both groups (10 mg/kg, administered subcutaneously).…”

Section: Reversion Of M184v In Vivomentioning

confidence: 99%

Reversion of the M184V Mutation in Simian Immunodeficiency Virus Reverse Transcriptase Is Selected by Tenofovir, Even in the Presence of Lamivudine

Murry¹,

Higgins²,

Matthews³

et al. 2003

J Virol

View full text Add to dashboard Cite

The methionine-to-valine mutation in codon 184 (M184V) in reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) or simian immunodeficiency virus (SIV) confers resistance to (؊)-2-deoxy-3-thiacytidine (3TC; lamivudine) and increased sensitivity to 9-[2-(phosphonomethoxy)propyl]adenine (PMPA; tenofovir). We have used the SIV model to evaluate the effect of the M184V mutation on the emergence of resistance to the combination of 3TC plus PMPA. A site-directed mutant of SIVmac239 containing M184V (SIVmac239-184V) was used to select for resistance to both 3TC and PMPA by serial passage in the presence of increasing concentrations of both drugs. Under these selection conditions, the M184V mutation reverted in the majority of the selections. Variants resistant to both drugs were found to have the lysine-to-arginine mutation at codon 65 (K65R), which has previously been associated with resistance to PMPA in both SIV and HIV. Similarly, in rhesus macaques infected with SIVmac239-184V for 46 weeks and treated daily with The rapid emergence of drug-resistant mutants of human immunodeficiency virus (HIV) has proven to be a major obstacle in antiviral therapy for AIDS (7,32,36,63). Even highly active antiretroviral therapy has been limited by the emergence of multidrug-resistant HIV (32,46,61). This has led to efforts to identify drug combinations in which resistance to one drug results in a mutant virus that suppresses normal resistance to a second drug or in a mutant virus that is hypersensitive to other drugs (2,27,28,35,52).One mutation that results in phenotypic changes in HIV type 1 (HIV-1) that are useful in certain drug combinations is the methionine-to-valine mutation in codon 184 (M184V) of reverse transcriptase (RT). This mutation arises rapidly in therapy with the oxathiolane nucleosides, (Ϫ)-2Ј-deoxy-3Ј-thiacytidine (3TC; lamivudine) and (Ϫ)-2Ј-deoxy-5-fluoro-3Ј-thiacytidine [(Ϫ)-FTC], and results in high-level (Ͼ100-fold) resistance to these drugs (49,55). This is often preceded by emergence of a methionine-to-isoleucine mutation in codon 184 (M184I), which is quickly replaced by M184V (22, 50). This M184V mutation is located in the highly conserved YMDD motif of RT, which is directly involved in binding the incoming nucleotide during reverse transcription (19,20,24,53). It results in decreased processivity (1,3,21,23,51) and increased fidelity (11,41,62) of the DNA polymerase activity of RT in biochemical assays. However, the increase in fidelity was less than twofold in an M13 phage-based assay that scored the overall mutation rate after transfection of RT products into bacteria (9). M184V mutants of HIV-1 also have reduced replication rates in certain cell lines (1, 35, 51), and they have a broad array of changes in susceptibility to nucleoside analogs (15,28,35,54,55,64).A major effect of the M184V mutation is to suppress phenotypic resistance to 3Ј-azido-3Ј-deoxythymidine (AZT; zidovudine) when M184V is present along with mutations that normally confer resistance to AZT (28,55). Clinical...

show abstract

Section: Reversion Of M184v In Vivomentioning

confidence: 99%

Reversion of the M184V Mutation in Simian Immunodeficiency Virus Reverse Transcriptase Is Selected by Tenofovir, Even in the Presence of Lamivudine

Murry¹,

Higgins²,

Matthews³

et al. 2003

J Virol

View full text Add to dashboard Cite

show abstract

“…Interestingly, L-FddC showed the highest selectivity index (SI; SI = 9,000) compared with those for L-ddC (SI = 37), 3-D-2',3'-dideoxy-5-fluorocytidine (D-FddC; SI = 35), and 3'-azido-3'-deoxythymidine (AZT; SI = 100) when the index was determined relative to that for toxicity to human bone marrow progenitor cells (14). L-ddC and L-FddC demonstrated a cross-resistance to HIV-1 variants resistant to 2',3'-dideoxy-3'-thiacytidine (3TC; BCH-189) and its 5-fluoro-derivative (FTC) (14). Mutations of the reverse transcriptase (RT) at codon 184 from methionine (ATG, Met) to valine (GTG or GTA, Val) or isoleucine (ATA, Ile) have been generated through in vitro selection with 3TC or FTC (11,12,23).…”

mentioning

confidence: 99%

“…L-FddC potently inhibited HIV-1 and HIV-2 replication in vitro in various cell lines and exhibited a 90% effective concentration of 0.15 ,uM in human peripheral blood mononuclear cells infected with HIV-1 (14). Interestingly, L-FddC showed the highest selectivity index (SI; SI = 9,000) compared with those for L-ddC (SI = 37), 3-D-2',3'-dideoxy-5-fluorocytidine (D-FddC; SI = 35), and 3'-azido-3'-deoxythymidine (AZT; SI = 100) when the index was determined relative to that for toxicity to human bone marrow progenitor cells (14). L-ddC and L-FddC demonstrated a cross-resistance to HIV-1 variants resistant to 2',3'-dideoxy-3'-thiacytidine (3TC; BCH-189) and its 5-fluoro-derivative (FTC) (14).…”

mentioning

confidence: 99%

“…(-)-13-L-2',3'-Dideoxycytidine (L-ddC) and its 5-fluoro derivative (L-FddC) have been shown to have potent antiviral activities against human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) and human hepatitis B virus (HBV) in vitro (13,14,18,22,25). L-FddC potently inhibited HIV-1 and HIV-2 replication in vitro in various cell lines and exhibited a 90% effective concentration of 0.15 ,uM in human peripheral blood mononuclear cells infected with HIV-1 (14).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of human immunodeficiency virus type 1 reverse transcriptase by the 5'-triphosphate beta enantiomers of cytidine analogs

Faraj

Agrofoglio

Wakefield

et al. 1994

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

through in vitro selection with 3TC or FTC (11,12,23). DNA sequence analysis of the RT gene amplified from a patient who had received 3TC therapy for 4 months revealed a mixture of the mutation at codon 184 from Met to Val (M184V) and the parental genotype, indicating that the mutation at the methionine at codon 184 (Met-184) can occur in vivo (23). In order to understand the mechanisms of action and drug resistance, the 5'-triphosphates of L-ddC (L-ddCTP) and L-FddC (LFddCTP) were synthesized, and the inhibitory effects of these triphosphate derivatives toward HIV-1 RT recombinant wildtype (WT) (WT RT) and the site-directed mutagenesis recom-

show abstract

“…(Ϫ)-FTC is a 3TC analog with stronger in vitro activity and an improved pharmacokinetic profile (19,21,50). HIV-1 variants resistant to these drugs occur predominantly from a methionine-tovaline mutation in position 184 (M184V) of RT, although a mutation to isoleucine (M184I) also occurs transiently (28,53).…”

mentioning

confidence: 99%

Virulence and Reduced Fitness of Simian Immunodeficiency Virus with the M184V Mutation in Reverse Transcriptase

Rompay

Matthews²,

Higgins³

et al. 2002

J Virol

View full text Add to dashboard Cite

. The two SIVmac239-184V-infected animals of group C did not receive any drug treatment, and in both animals the virus population reverted to predominantly wild type (184M) by 8 weeks after inoculation. The other five SIVmac239-184V-infected animals (group B) were treated with (؊)-FTC to prevent reversion. Although virus levels 1 week after inoculation were lower in the SIVmac239-184V-infected macaques than in the SIVmac239-infected animals, no significant differences were observed from week 2 onwards. Two animals in each group developed AIDS and were euthanized, while all other animals were clinically stable at 46 weeks of infection. These data demonstrate that the M184V mutation in SIV conferred a slightly reduced fitness but did not affect disease outcome.

show abstract

Anti-human immunodeficiency virus activities of the beta-L enantiomer of 2',3'-dideoxycytidine and its 5-fluoro derivative in vitro

Cited by 131 publications

References 44 publications

Reversion of the M184V Mutation in Simian Immunodeficiency Virus Reverse Transcriptase Is Selected by Tenofovir, Even in the Presence of Lamivudine

Reversion of the M184V Mutation in Simian Immunodeficiency Virus Reverse Transcriptase Is Selected by Tenofovir, Even in the Presence of Lamivudine

Inhibition of human immunodeficiency virus type 1 reverse transcriptase by the 5'-triphosphate beta enantiomers of cytidine analogs

Virulence and Reduced Fitness of Simian Immunodeficiency Virus with the M184V Mutation in Reverse Transcriptase

Contact Info

Product

Resources

About